10-79557276-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001098668.4(SFTPA2):c.680T>G(p.Met227Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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 Likely_pathogenic. Variant got 8 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.680T>G	p.Met227Arg	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.680T>G	p.Met227Arg	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9	c.680T>G	p.Met227Arg	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 06, 2020

The p.Met227Arg variant substitutes the methionine for arginine at position 227 within the last exon of SFTPA2. This variant has not been observed in large population cohorts (0 of 251,474 alleles; Genome Aggregation Database v2.1). This variant is absent from the medical literature and the patient database ClinVar. This is a moderately conserved amino acid. Some in silico tools predict this change is damaging (EIGEN, FATHMM-MKL, MutationTaster and SIFT), while others predict this change is tolerated (DANN, M-CAP, MVP, PrimateAI and REVEL). SFTPA2 encodes the pulmonary-associated surfactant protein A2. The 248-amino acid (aa) SFTPA2 protein contains a collagen-like region (aa 28-99), a neck domain (aa 100-133), and a C-terminal carbohydrate-recognition domain (aa 134-248) (PMID: 23056344 and UniProtKB - Q8IWL1). Pathogenic variants (p.Gly231Val; p.Gly231Arg) and benign variants (p.Gln 223Lys) have been reported in this region of the carbohydrate-recognition domain (PMID: 26568241). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.015	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.84
MutPred		0.84		Loss of stability (P = 0.0577);Loss of stability (P = 0.0577);
MVP		0.73
MPC		2.6
ClinPred		1.0	D
GERP RS		2.8
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-81317032;