10-79557264-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G231R) has been classified as Likely pathogenic.

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a disulfide_bond (size 14) in uniprot entity SFPA2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001098668.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-79557265-C-T is described in Lovd as [Likely_pathogenic].
• 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 [Likely_risk_allele]. Clinvar id is 13199.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele]. Variant chr10-79557264-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.692G>T	p.Gly231Val	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.692G>T	p.Gly231Val	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9	c.692G>T	p.Gly231Val	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2009

- -

Pulmonary fibrosis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

- -

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
MutationTaster	Benign	1.0	A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917737; hg19: chr10-81317020;