10-79557289-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001098668.4(SFTPA2):c.667C>A(p.Gln223Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,734 control chromosomes in the GnomAD database, including 38,163 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 0.25 ( 5277 hom., cov: 32)

Exomes 𝑓: 0.21 ( 32886 hom. )

Consequence

SFTPA2
NM_001098668.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.945

Publications

65 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 -18 ACMG points.

PM1

In a domain C-type lectin (size 116) in uniprot entity SFPA2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001098668.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0025300682).

BP6

Variant 10-79557289-G-T is Benign according to our data. Variant chr10-79557289-G-T is described in ClinVar as Benign. ClinVar VariationId is 227071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA2	NM_001098668.4 link	c.667C>A	p.Gln223Lys	missense_variant	Exon 6 of 6	ENST00000372325.7	NP_001092138.1	Q8IWL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SFTPA2	ENST00000372325.7 link	c.667C>A	p.Gln223Lys	missense_variant	Exon 6 of 6	1	NM_001098668.4	ENSP00000361400.2	Q8IWL1
SFTPA2	ENST00000372327.9 link	c.667C>A	p.Gln223Lys	missense_variant	Exon 5 of 5	1		ENSP00000361402.5	Q8IWL1
SFTPA2	ENST00000417041.1 link	c.*193C>A		downstream_gene_variant		5		ENSP00000397375.1	X6REF7

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37959

AN:

151766

Hom.:

5265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.370

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.245

GnomAD2 exomes

AF:

0.217

AC:

54596

AN:

251408

AF XY:

0.223

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.201

Gnomad OTH exome

AF:

0.202

GnomAD4 exome

AF:

0.207

AC:

301937

AN:

1461850

Hom.:

32886

Cov.:

AF XY:

0.210

AC XY:

152941

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.385

AC:

12871

AN:

33474

American (AMR)

AF:

0.137

AC:

6125

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

8075

AN:

26136

East Asian (EAS)

AF:

0.196

AC:

7763

AN:

39700

South Asian (SAS)

AF:

0.289

AC:

24887

AN:

86250

European-Finnish (FIN)

AF:

0.215

AC:

11480

AN:

53416

Middle Eastern (MID)

AF:

0.320

AC:

1843

AN:

5768

European-Non Finnish (NFE)

AF:

0.194

AC:

215836

AN:

1111994

Other (OTH)

AF:

0.216

AC:

13057

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

18713

37425

56138

74850

93563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7550

15100

22650

30200

37750

<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:

0.250

AC:

38017

AN:

151884

Hom.:

5277

Cov.:

AF XY:

0.249

AC XY:

18518

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.370

AC:

15324

AN:

41362

American (AMR)

AF:

0.165

AC:

2524

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1059

AN:

3472

East Asian (EAS)

AF:

0.188

AC:

975

AN:

5178

South Asian (SAS)

AF:

0.269

AC:

1298

AN:

4818

European-Finnish (FIN)

AF:

0.206

AC:

2174

AN:

10538

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.205

AC:

13937

AN:

67932

Other (OTH)

AF:

0.244

AC:

515

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1358

2716

4075

5433

6791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.229

Hom.:

2278

Bravo

AF:

0.248

TwinsUK

AF:

0.190

AC:

705

ALSPAC

AF:

0.188

AC:

724

ESP6500AA

AF:

0.358

AC:

1576

ESP6500EA

AF:

0.200

AC:

1718

ExAC

AF:

0.222

AC:

26906

EpiCase

AF:

0.215

EpiControl

AF:

0.212

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26436397, 24950659, 16292672, 23056344, 20466729) -

not specified

Benign:1

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln223Lys in exon 6 of SFTPA2: This variant is not expected to have clinical s ignificance because it has been identified in 36% (1576/4406) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1965708). -

Interstitial lung disease 2

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.20

(source)

DANN

Benign

0.30

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0024

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.90

PhyloP100

-0.94

PrimateAI

Benign

0.37

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.014

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.047

MPC

1.3

ClinPred

0.0031

GERP RS

-3.2

gMVP

0.50

Mutation Taster

=95/5

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