rs1059056

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005411.5(SFTPA1):c.342T>C(p.Phe114Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 151,880 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 26 hom. )

Failed GnomAD Quality Control

Consequence

SFTPA1
NM_005411.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.00900

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 10-79613238-T-C is Benign according to our data. Variant chr10-79613238-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.009 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00363 (551/151880) while in subpopulation EAS AF = 0.025 (128/5120). AF 95% confidence interval is 0.0215. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA1	NM_005411.5 link	c.342T>C	p.Phe114Phe	synonymous_variant	Exon 5 of 6	ENST00000398636.8	NP_005402.3	Q8IWL2-1A0A024QZP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SFTPA1	ENST00000398636.8 link	c.342T>C	p.Phe114Phe	synonymous_variant	Exon 5 of 6	1	NM_005411.5	ENSP00000381633.3	Q8IWL2-1
SFTPA1	ENST00000419470.6 link	c.387T>C	p.Phe129Phe	synonymous_variant	Exon 5 of 6	1		ENSP00000397082.2	Q8IWL2-2
SFTPA1	ENST00000428376.6 link	c.342T>C	p.Phe114Phe	synonymous_variant	Exon 4 of 5	1		ENSP00000411102.2	Q8IWL2-1
SFTPA1	ENST00000429958.5 link	c.342T>C	p.Phe114Phe	synonymous_variant	Exon 4 of 5	1		ENSP00000395527.1	A0A0C4DG36

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

550

AN:

151762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0255

Gnomad SAS

AF:

0.00728

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.000810

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00287

AC:

721

AN:

250964

AF XY:

0.00291

show subpopulations

Gnomad AFR exome

AF:

0.00525

Gnomad AMR exome

AF:

0.000955

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.0166

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00140

AC:

2042

AN:

1460432

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1125

AN XY:

726560

show subpopulations

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

African (AFR)

AF:

0.00486

AC:

162

AN:

33328

American (AMR)

AF:

0.00105

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26108

East Asian (EAS)

AF:

0.0168

AC:

660

AN:

39390

South Asian (SAS)

AF:

0.00569

AC:

489

AN:

85994

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00819

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000366

AC:

407

AN:

1111512

Other (OTH)

AF:

0.00181

AC:

109

AN:

60274

⚠️ 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: 0.382

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00363

AC:

551

AN:

151880

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

285

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00681

AC:

282

AN:

41380

American (AMR)

AF:

0.00150

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.0250

AC:

128

AN:

5120

South Asian (SAS)

AF:

0.00750

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000810

AC:

AN:

67912

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00226

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe129Phe in exon 5 of SFTPA1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 4.0% (8/200) of Han Chinese chromosomes from a broad population by the 1000 Genomes Project (http:/ /www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs1059056). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.0090

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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