10-79557300-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001098668.4(SFTPA2):c.656G>T(p.Arg219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.340

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain C-type lectin (size 116) in uniprot entity SFPA2_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) in NM_001098668.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10345444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.656G>T	p.Arg219Leu	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.656G>T	p.Arg219Leu	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9	c.656G>T	p.Arg219Leu	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Interstitial lung disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Alder lab, University of Pittsburgh

Feb 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.5
Dann	Benign	0.85
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0078	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.013
Sift	Benign	0.071	T;T
Sift4G	Uncertain	0.053	T;T
Vest4		0.15
MutPred		0.36		Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);
MVP		0.13
MPC		1.3
ClinPred		0.043	T
GERP RS		-0.91
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs777910370; hg19: chr10-81317056;