Genetic Variant SFTPA1:c.-23-5T>C (chr10-79611798-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005411.5(SFTPA1):c.-23-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SFTPA1
NM_005411.5 splice_region, intron

Scores

Splicing: ADA: 0.0001247

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.30

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA1	NM_005411.5 link	c.-23-5T>C		splice_region_variant, intron_variant	Intron 2 of 5	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.-23-5T>C		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_005411.5	ENSP00000381633.3		Q8IWL2-1

Frequencies

GnomAD3 genomes

AF:

0.0000162

AC:

AN:

123646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000370

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1338326

Hom.:

Cov.:

105

AF XY:

0.0000135

AC XY:

AN XY:

664708

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30992

American (AMR)

AF:

0.00

AC:

AN:

38906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23172

East Asian (EAS)

AF:

0.00

AC:

AN:

35464

South Asian (SAS)

AF:

0.00

AC:

AN:

78616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5164

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1024466

Other (OTH)

AF:

0.0000183

AC:

AN:

54600

⚠️ 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: 0.331

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000162

AC:

AN:

123646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35474

American (AMR)

AF:

0.00

AC:

AN:

12296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2908

East Asian (EAS)

AF:

0.00

AC:

AN:

4132

South Asian (SAS)

AF:

0.00

AC:

AN:

3826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.0000370

AC:

AN:

54026

Other (OTH)

AF:

0.00

AC:

AN:

1674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.46

(source)

DANN

Benign

0.63

PhyloP100

-1.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.020

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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10-79611798-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over