rs1965708

chr10-79557289-G-T

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.667C>A(p.Gln223Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,734 control chromosomes in the GnomAD database, including 38,163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5277 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32886 hom.)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.945

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 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025300682).
• BP6: Variant 10-79557289-G-T is Benign according to our data. Variant chr10-79557289-G-T is described in ClinVar as [Benign]. Clinvar id is 227071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-79557289-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.667C>A	p.Gln223Lys	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.667C>A	p.Gln223Lys	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9	c.667C>A	p.Gln223Lys	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37959 AN: 151766 Hom.: 5265 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.217 AC: 54596 AN: 251408 Hom.: 6547 AF XY: 0.223 AC XY: 30291 AN XY: 135878

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.192

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.207 AC: 301937 AN: 1461850 Hom.: 32886 Cov.: 34 AF XY: 0.210 AC XY: 152941 AN XY: 727230

Gnomad4 AFR exome AF: 0.385

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.250 AC: 38017 AN: 151884 Hom.: 5277 Cov.: 32 AF XY: 0.249 AC XY: 18518 AN XY: 74222

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.244

Alfa AF: 0.228 Hom.: 1549

Bravo AF: 0.248

TwinsUK AF: 0.190 AC: 705

ALSPAC AF: 0.188 AC: 724

ESP6500AA AF: 0.358 AC: 1576

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.222 AC: 26906

EpiCase AF: 0.215

EpiControl AF: 0.212

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Nov 26, 2014

p.Gln223Lys in exon 6 of SFTPA2: This variant is not expected to have clinical s ignificance because it has been identified in 36% (1576/4406) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1965708). -

Interstitial lung disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2020

This variant is associated with the following publications: (PMID: 26436397, 24950659, 16292672, 23056344, 20466729) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.20
Dann	Benign	0.30
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0024	N
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.014
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.047
MPC		1.3
ClinPred		0.0031	T
GERP RS		-3.2
gMVP		0.50

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: rs1965708; hg19: chr10-81317045; COSMIC: COSV64882436; COSMIC: COSV64882436;