10-79611881-T-C

Position:

chr10-79611881-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005411.5(SFTPA1):c.56T>C(p.Val19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 1,431,716 control chromosomes in the GnomAD database, including 6,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.088 ( 578 hom., cov: 32)

Exomes 𝑓: 0.087 ( 6006 hom. )

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.457

Variant links:

Genes affected

SFTPA1 (HGNC:10798): (surfactant protein A1) This gene encodes a lung surfactant protein that is a member of a subfamily of C-type lectins called collectins. The encoded protein binds specific carbohydrate moieties found on lipids and on the surface of microorganisms. This protein plays an essential role in surfactant homeostasis and in the defense against respiratory pathogens. Mutations in this gene are associated with idiopathic pulmonary fibrosis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

SFTPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017886162).

BP6

Variant 10-79611881-T-C is Benign according to our data. Variant chr10-79611881-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPA1	NM_005411.5 linkuse as main transcript	c.56T>C	p.Val19Ala	missense_variant	3/6	ENST00000398636.8	NP_005402.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8 linkuse as main transcript	c.56T>C	p.Val19Ala	missense_variant	3/6	1	NM_005411.5	ENSP00000381633	P1	Q8IWL2-1

Frequencies

GnomAD3 genomes

AF:

0.0883

AC:

10823

AN:

122556

Hom.:

571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0279

Gnomad AMI

AF:

0.0169

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.0949

Gnomad EAS

AF:

0.0249

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.0777

Gnomad MID

AF:

0.0833

Gnomad NFE

AF:

0.0941

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.0779

AC:

18458

AN:

237012

Hom.:

1906

AF XY:

0.0782

AC XY:

10002

AN XY:

127874

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.0487

Gnomad EAS exome

AF:

0.0134

Gnomad SAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.0434

Gnomad NFE exome

AF:

0.0530

Gnomad OTH exome

AF:

0.0790

GnomAD4 exome

AF:

0.0866

AC:

113321

AN:

1309066

Hom.:

6006

Cov.:

121

AF XY:

0.0892

AC XY:

58301

AN XY:

653952

show subpopulations

Gnomad4 AFR exome

AF:

0.0192

Gnomad4 AMR exome

AF:

0.243

Gnomad4 ASJ exome

AF:

0.0778

Gnomad4 EAS exome

AF:

0.0271

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.0555

Gnomad4 NFE exome

AF:

0.0773

Gnomad4 OTH exome

AF:

0.0855

GnomAD4 genome

AF:

0.0884

AC:

10846

AN:

122650

Hom.:

578

Cov.:

AF XY:

0.0932

AC XY:

5576

AN XY:

59842

show subpopulations

Gnomad4 AFR

AF:

0.0279

Gnomad4 AMR

AF:

0.215

Gnomad4 ASJ

AF:

0.0949

Gnomad4 EAS

AF:

0.0249

Gnomad4 SAS

AF:

0.244

Gnomad4 FIN

AF:

0.0777

Gnomad4 NFE

AF:

0.0941

Gnomad4 OTH

AF:

0.113

Alfa

AF:

0.0832

Hom.:

ExAC

AF:

0.0923

AC:

11209

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2015

This is a homologous region and while the NGS call looks real we do not have a S anger primer pair where both primers are unique. The origin of this variant can not be unambiguously assigned and therefore it is excluded from patient reports. LMM is in the process of exuding repetitive regions where Sanger confirmation is not possible from tests (pending). p.Val34Ala in exon 3 of SFTPA1: This var iant was detected at high frequency in large cohorts sequenced by the ExAC conso rtium (http://exac.broadinstitute.org/). While the frequencies are high enough to rule out a pathogneic role the data did not pass quality filters. Other data supporting a benign role include to a lack of conservation across species, inclu ding mammals. Of note, the gorilla, orangutan, gibbon, rhesus, crab eating macaq ue, baboon, and green monkey have an alanine (Ala) at this position. In additio n, computational prediction tools do not suggest a high likelihood of impact to the protein. -

See cases

Benign:1

Likely benign, no assertion criteria provided

case-control

Department of Pediatrics, Penn State Hershey College of Medicine

- -

SFTPA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2024

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

0.060

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.034

DANN

Benign

0.23

DEOGEN2

Benign

0.042

T;T;.;.;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.049

.;T;T;.;T

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

L;L;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

0.10

N;N;N;N;N

REVEL

Benign

0.027

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.84

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.074

MPC

0.017

ClinPred

0.0064

GERP RS

-5.3

Varity_R

0.018

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

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