NM_001098668.4:c.532G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2

The NM_001098668.4(SFTPA2):c.532G>A(p.Val178Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SFTPA2
NM_001098668.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.94

Variant links:

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]

SFTPA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a disulfide_bond (size 91) in uniprot entity SFPA2_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001098668.4

PP5

Variant 10-79557424-C-T is Pathogenic according to our data. Variant chr10-79557424-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 985062.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA2	NM_001098668.4 link	c.532G>A	p.Val178Met	missense_variant	Exon 6 of 6	ENST00000372325.7	NP_001092138.1	Q8IWL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA2	ENST00000372325.7 link	c.532G>A	p.Val178Met	missense_variant	Exon 6 of 6	1	NM_001098668.4	ENSP00000361400.2		Q8IWL1
SFTPA2	ENST00000372327.9 link	c.532G>A	p.Val178Met	missense_variant	Exon 5 of 5	1		ENSP00000361402.5		Q8IWL1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250974

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease 2

Pathogenic:3

Feb 01, 2022

Alder lab, University of Pittsburgh

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PS4_Moderate+PP1+PP4 -

Nov 18, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Sep 20, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate V178M results in impaired SFTPA2 secretion (Tsui et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26568241, 31796085, 25553246, 30854216, 32855221) -

Inborn genetic diseases

Uncertain:1

Dec 20, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.0037

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0040

D;D

Vest4

0.49

MVP

0.53

MPC

1.9

ClinPred

0.86

GERP RS

3.0

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over