NM_005411.5(SFTPA1):c.292G>A (p.Gly98Arg) AND Proximal 16p11.2 microdeletion syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 8, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002254435.2

Allele description [Variation Report for NM_005411.5(SFTPA1):c.292G>A (p.Gly98Arg)]

NM_005411.5(SFTPA1):c.292G>A (p.Gly98Arg)

Gene:

SFTPA1:surfactant protein A1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.3

Genomic location:

Preferred name:

NM_005411.5(SFTPA1):c.292G>A (p.Gly98Arg)

HGVS:

NC_000010.11:g.79612431G>A
NG_021189.1:g.6493G>A
NM_001093770.3:c.337G>A
NM_001164644.2:c.292G>A
NM_001164645.2:c.190G>A
NM_001164646.2:c.145G>A
NM_001164647.1:c.292G>A
NM_005411.5:c.292G>AMANE SELECT
NP_001087239.2:p.Gly113Arg
NP_001158116.1:p.Gly98Arg
NP_001158117.1:p.Gly64Arg
NP_001158118.1:p.Gly49Arg
NP_001158119.1:p.Gly98Arg
NP_005402.3:p.Gly98Arg
NC_000010.10:g.81372187G>A
NM_005411.4:c.292G>A

Protein change:

G113R

Links:

dbSNP: rs1589239722

NCBI 1000 Genomes Browser:

rs1589239722

Molecular consequence:

NM_001093770.3:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164644.2:c.292G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164645.2:c.190G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164646.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164647.1:c.292G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005411.5:c.292G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Proximal 16p11.2 microdeletion syndrome
Synonyms:: 16p11.2 deletion syndrome; CHROMOSOME 16p11.2 DELETION SYNDROME, 593-KB; Chromosome 16p11.2 deletion syndrome; See all synonyms [MedGen]
Identifiers:: Gene: 100187724; MONDO: MONDO:0012756; MedGen: C3150154; Orphanet: 261197; OMIM: 611913

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525599	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525599

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 8, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002525599.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is currently absent from large population controls, patient databases, and the medical literature (Genome Aggregation Database [GnomAD], ClinVar, HGMD). The c.292G>A change is in the last nucleotide (3' end) of exon 4 (NM_005411.4, total 6 exons). It is predicted to substitute the glycine at position 98 with arginine within the collagen-like domain of the protein. Its possible impact on splicing is unknown. In silico splice site prediction tools predict this change will affect splicing, but there is currently no functional data to support these predictions (Human Splicing Finder, Transcript Inferred Pathogenicity Score). This nucleotide position is semi-conserved across species (GERP 2.73) and the p.Gly98Arg change is predicted to be damaging by multiple in silico missense prediction tools (MutationTaster, MutationAssessor, FATHMM, SIFT). There is emerging evidence to support SFTPA1 pathogenic variantsas a rare cause of familial idiopathic pulmonary fibrosis and idiopathic interstitial pneumonia (PMID: 30854216, 26792177, 29977744, 31601679). All pathogenic sequencing variants reported to date have been missense changes. Both autosomal dominant with incomplete penetrance and recessive inheritance models have been proposed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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