10-79559336-C-G

Position:

• chr10-79559336-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001098668.4(SFTPA2):​c.148G>C​(p.Val50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,531,982 control chromosomes in the GnomAD database, including 2,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (173 hom., cov: 28)
  • Exomes 𝑓: 0.023 (2528 hom.)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Pulmonary surfactant-associated protein A2 (size 227) in uniprot entity SFPA2_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_001098668.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0046575665).
• BP6: Variant 10-79559336-C-G is Benign according to our data. Variant chr10-79559336-C-G is described in ClinVar as [Benign]. Clinvar id is 227065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPA2	NM_001098668.4	c.148G>C	p.Val50Leu	missense_variant	3/6	ENST00000372325.7	NP_001092138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPA2	ENST00000372325.7	c.148G>C	p.Val50Leu	missense_variant	3/6	1	NM_001098668.4	ENSP00000361400.2
SFTPA2	ENST00000372327.9	c.148G>C	p.Val50Leu	missense_variant	2/5	1		ENSP00000361402.5
SFTPA2	ENST00000417041.1	c.148G>C	p.Val50Leu	missense_variant	3/6	5		ENSP00000397375.1
SFTPA2	ENST00000492049.1	c.148G>C	p.Val50Leu	missense_variant	1/2	5		ENSP00000473275.1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6255 AN: 151814 Hom.: 172 Cov.: 28

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0558

Gnomad EAS AF: 0.00580

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0625

Gnomad OTH AF: 0.0490

GnomAD3 exomes AF: 0.0247 AC: 5945 AN: 241058 Hom.: 300 AF XY: 0.0265 AC XY: 3436 AN XY: 129744

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.00267

Gnomad SAS exome AF: 0.0305

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0233 AC: 32182 AN: 1380050 Hom.: 2528 Cov.: 32 AF XY: 0.0247 AC XY: 16998 AN XY: 687524

Gnomad4 AFR exome AF: 0.00806

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0424

Gnomad4 EAS exome AF: 0.00255

Gnomad4 SAS exome AF: 0.0373

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0282

GnomAD4 genome AF: 0.0412 AC: 6256 AN: 151932 Hom.: 173 Cov.: 28 AF XY: 0.0399 AC XY: 2963 AN XY: 74258

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0558

Gnomad4 EAS AF: 0.00601

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0340

Gnomad4 NFE AF: 0.0625

Gnomad4 OTH AF: 0.0480

Alfa AF: 0.0315 Hom.: 25

Bravo AF: 0.0398

ExAC AF: 0.0400 AC: 4860

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 12, 2015

p.Val50Leu in exon 3 of SFTPA2: This variant is not expected to have clinical si gnificance it has been identified in 5% (3378/62636) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 192907309). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.034
DANN	Benign	0.71
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.17	.;.;T;T
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.61	N;N;N;.
REVEL	Benign	0.027
Sift	Benign	0.69	T;T;T;.
Sift4G	Benign	0.47	T;T;T;.
Vest4		0.049
MPC		1.6
ClinPred		0.0026	T
GERP RS		-4.2
gMVP		0.15

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: rs192907309; hg19: chr10-81319092; COSMIC: COSV64882108; COSMIC: COSV64882108;