10-79611851-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005411.5(SFTPA1):c.26A>C(p.Asn9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,692 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 25 hom., cov: 34)

Exomes 𝑓: 0.00085 ( 19 hom. )

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.57

Publications

5 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040893555).

BP6

Variant 10-79611851-A-C is Benign according to our data. Variant chr10-79611851-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00827 (1259/152210) while in subpopulation AFR AF = 0.0283 (1175/41474). AF 95% confidence interval is 0.027. There are 25 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA1	NM_005411.5 link	c.26A>C	p.Asn9Thr	missense_variant	Exon 3 of 6	ENST00000398636.8	NP_005402.3	Q8IWL2-1A0A024QZP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8 link	c.26A>C	p.Asn9Thr	missense_variant	Exon 3 of 6	1	NM_005411.5	ENSP00000381633.3		Q8IWL2-1

Frequencies

GnomAD3 genomes

AF:

0.00825

AC:

1255

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00121

AC:

304

AN:

250754

AF XY:

0.000885

show subpopulations

Gnomad AFR exome

AF:

0.0159

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000850

AC:

1242

AN:

1461482

Hom.:

Cov.:

124

AF XY:

0.000722

AC XY:

525

AN XY:

727060

show subpopulations

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

African (AFR)

AF:

0.0275

AC:

918

AN:

33372

American (AMR)

AF:

0.00150

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000756

AC:

AN:

1111792

Other (OTH)

AF:

0.00244

AC:

147

AN:

60366

⚠️ 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: 0.370

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00827

AC:

1259

AN:

152210

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

557

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0283

AC:

1175

AN:

41474

American (AMR)

AF:

0.00373

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68012

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00436

Hom.:

Bravo

AF:

0.00984

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00200

AC:

243

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn24Thr in exon 3 of SFTPA1: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >10 mammals have a threonine (Thr) at this position. In addition, computati onal prediction tools do not suggest a high likelihood of impact to the protein. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.030

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.043

T;T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.000060

LIST_S2

Benign

0.051

.;T;T;.;T

MetaRNN

Benign

0.0041

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

N;N;.;.;.

PhyloP100

-1.6

PrimateAI

Benign

0.47

PROVEAN

Benign

1.2

N;N;N;N;N

REVEL

Benign

0.016

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.11

MVP

0.055

MPC

0.017

ClinPred

0.0061

GERP RS

1.6

Varity_R

0.029

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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10-79611851-A-C

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