10-79559458-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21170 hom., cov: 27)

Exomes 𝑓: 0.61 ( 259587 hom. )

Consequence

SFTPA2
NM_001098668.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.14

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

interstitial lung disease 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
idiopathic pulmonary fibrosis
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp

SFTPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 227066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SFTPA2	NM_001098668.4 link	c.26C>A	p.Thr9Asn	missense_variant	Exon 3 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.26C>A	p.Thr9Asn	missense_variant	Exon 3 of 6	1	NM_001098668.4	ENSP00000361400.2		Q8IWL1

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

77988

AN:

149154

Hom.:

21171

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.455

AC:

84524

AN:

185672

AF XY:

0.451

show subpopulations

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 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.:

AF XY:

0.604

AC XY:

363151

AN XY:

600936

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.349

AC:

9836

AN:

28202

American (AMR)

AF:

0.501

AC:

19901

AN:

39718

Ashkenazi Jewish (ASJ)

AF:

0.422

AC:

9786

AN:

23208

East Asian (EAS)

AF:

0.535

AC:

19542

AN:

36550

South Asian (SAS)

AF:

0.443

AC:

34136

AN:

77118

European-Finnish (FIN)

AF:

0.574

AC:

29271

AN:

50954

Middle Eastern (MID)

AF:

0.356

AC:

1815

AN:

5102

European-Non Finnish (NFE)

AF:

0.653

AC:

580273

AN:

888690

Other (OTH)

AF:

0.570

AC:

29372

AN:

51502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.328

Heterozygous variant carriers

16689

33378

50067

66756

83445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12930

25860

38790

51720

64650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.523

AC:

77999

AN:

149268

Hom.:

21170

Cov.:

AF XY:

0.516

AC XY:

37536

AN XY:

72740

show subpopulations

African (AFR)

AF:

0.390

AC:

15796

AN:

40540

American (AMR)

AF:

0.504

AC:

7593

AN:

15062

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1478

AN:

3440

East Asian (EAS)

AF:

0.533

AC:

2655

AN:

4982

South Asian (SAS)

AF:

0.445

AC:

2097

AN:

4714

European-Finnish (FIN)

AF:

0.583

AC:

6010

AN:

10308

Middle Eastern (MID)

AF:

0.414

AC:

121

AN:

292

European-Non Finnish (NFE)

AF:

0.606

AC:

40565

AN:

66978

Other (OTH)

AF:

0.490

AC:

1011

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

1728

3455

5183

6910

8638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.520

Hom.:

7347

Bravo

AF:

0.517

ExAC

AF:

0.358

AC:

43356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

SFTPA2-related disorder

Benign:1

Apr 26, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.21

(source)

DANN

Benign

0.71

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.29

.;.;T;T;T

MetaRNN

Benign

0.00037

T;T;T;T;T

MetaSVM

Benign

-0.93

PhyloP100

-1.1

PrimateAI

Benign

0.40

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

GERP RS

0.64

PromoterAI

-0.014

Neutral

(source)

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over