10-79557496-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP5BP4BS2

The NM_001098668.4(SFTPA2):c.460G>C(p.Ala154Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SFTPA2
NM_001098668.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.82

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 -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

PP5

Variant 10-79557496-C-G is Pathogenic according to our data. Variant chr10-79557496-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1705909.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.13750714).. Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4 linkuse as main transcript	c.460G>C	p.Ala154Pro	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SFTPA2	ENST00000372325.7 linkuse as main transcript	c.460G>C	p.Ala154Pro	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9 linkuse as main transcript	c.460G>C	p.Ala154Pro	missense_variant	5/5	1		P1
SFTPA2	ENST00000417041.1 linkuse as main transcript	c.460G>C	p.Ala154Pro	missense_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249298

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.000130

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:

0.0000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1461434

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.000240

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000132

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000280

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Alder lab, University of Pittsburgh

Feb 01, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SFTPA2: PS3:Supporting, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.83

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0044

M_CAP

Benign

0.036

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.31

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.089

T;T;T

Sift4G

Benign

0.088

T;T;T

Vest4

0.28

MVP

0.23

MPC

1.8

ClinPred

0.093

GERP RS

-3.4

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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