rs3199725

chr10-79559458-G-Tchr10-79559458-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001098668.4(SFTPA2):c.26C>A(p.Thr9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,350,312 control chromosomes in the GnomAD database, including 280,757 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (21170 hom., cov: 27)
  • Exomes 𝑓: 0.61 (259587 hom.)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.684461E-4).
• BP6: Variant 10-79559458-G-T is Benign according to our data. Variant chr10-79559458-G-T is described in ClinVar as [Benign]. Clinvar id is 227066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-79559458-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.26C>A	p.Thr9Asn	missense_variant	3/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.26C>A	p.Thr9Asn	missense_variant	3/6	1	NM_001098668.4	P1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 77988 AN: 149154 Hom.: 21171 Cov.: 27

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.756

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.494

GnomAD3 exomes AF: 0.455 AC: 84524 AN: 185672 Hom.: 31716 AF XY: 0.451 AC XY: 44740 AN XY: 99180

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.431

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.529

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.483

GnomAD4 exome AF: 0.611 AC: 733932 AN: 1201044 Hom.: 259587 Cov.: 79 AF XY: 0.604 AC XY: 363151 AN XY: 600936

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.501

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.523 AC: 77999 AN: 149268 Hom.: 21170 Cov.: 27 AF XY: 0.516 AC XY: 37536 AN XY: 72740

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.490

Alfa AF: 0.490 Hom.: 3518

Bravo AF: 0.517

ExAC AF: 0.358 AC: 43356

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

Mar 12, 2015

p.Thr9Asn in exon 3 of SFTPA2: This variant is not expected to have clinical sig nificance it has been identified in 41% (22324/54314) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s1059046). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 24950659) -

SFTPA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.21
Dann	Benign	0.71
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
MetaRNN	Benign	0.00037	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N;N;N;.;.
REVEL	Benign	0.042
Sift	Benign	0.24	T;T;T;.;.
Sift4G	Benign	0.17	T;T;T;.;.
Vest4		0.13
MPC		1.6
ClinPred		0.018	T
GERP RS		0.64
gMVP		0.28

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: rs1059046; hg19: chr10-81319214; COSMIC: COSV64882118;