rs121917737

Variant names:

• chr10-79557264-C-A
• rs121917737
• NM_001098668.4:c.692G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001098668.4(SFTPA2):​c.692G>T​(p.Gly231Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Pathogenic/Likely risk allele no assertion criteria provided P:2
• Conservation: PhyloP100: 3.94
• Publications: 19 publications found

Genes affected

SFTPA2 (HGNC:10799): (surfactant protein A2) This gene is one of several genes encoding pulmonary-surfactant associated proteins (SFTPA) located on chromosome 10. Mutations in this gene and a highly similar gene located nearby, which affect the highly conserved carbohydrate recognition domain, are associated with idiopathic pulmonary fibrosis. The current version of the assembly displays only a single centromeric SFTPA gene pair rather than the two gene pairs shown in the previous assembly which were thought to have resulted from a duplication. [provided by RefSeq, Sep 2009]

SFTPA2 Gene-Disease associations (from GenCC):

• interstitial lung disease 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• idiopathic pulmonary fibrosis

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a domain C-type lectin (size 116) in uniprot entity SFPA2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001098668.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-79557264-C-A is Pathogenic according to our data. Variant chr10-79557264-C-A is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 13199.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA2	NM_001098668.4	c.692G>T	p.Gly231Val	missense_variant	Exon 6 of 6	ENST00000372325.7	NP_001092138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA2	ENST00000372325.7	c.692G>T	p.Gly231Val	missense_variant	Exon 6 of 6	1	NM_001098668.4	ENSP00000361400.2
SFTPA2	ENST00000372327.9	c.692G>T	p.Gly231Val	missense_variant	Exon 5 of 5	1		ENSP00000361402.5
SFTPA2	ENST00000417041.1	c.*218G>T		downstream_gene_variant		5		ENSP00000397375.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Interstitial lung disease 2 Pathogenic:1

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary fibrosis Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.35	D
PhyloP100		3.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.89
MutPred		0.96		Gain of solvent accessibility (P = 0.0713);Gain of solvent accessibility (P = 0.0713);
MVP		0.65
MPC		2.5
ClinPred		0.95	D
GERP RS		2.8
gMVP		0.91
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121917737; hg19: chr10-81317020;