10-79559511-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

The NM_001320813.2(SFTPA2):c.-26-2G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,434,494 control chromosomes in the GnomAD database, including 480,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39999 hom., cov: 28)

Exomes 𝑓: 0.81 ( 440365 hom. )

Consequence

SFTPA2
NM_001320813.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.7087

Clinical Significance

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

Conservation

PhyloP100: -1.31

Publications

22 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 -12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.26506025 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of 0 (no position change), new splice context is: gctcacggccatccctccAGcag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 10-79559511-C-T is Benign according to our data. Variant chr10-79559511-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320813.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SFTPA2	NM_001098668.4	MANE Select	c.-23-5G>A	splice_region intron	N/A	NP_001092138.1
SFTPA2	NM_001320814.1		c.8-5G>A	splice_region intron	N/A	NP_001307743.1
SFTPA2	NM_001320813.2		c.-26-2G>A	splice_acceptor intron	N/A	NP_001307742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.-23-5G>A	splice_region intron	N/A	ENSP00000361400.2
SFTPA2	ENST00000372327.9	TSL:1	c.-23-5G>A	splice_region intron	N/A	ENSP00000361402.5
SFTPA2	ENST00000640627.1	TSL:1	c.23-5G>A	splice_region intron	N/A	ENSP00000492537.1

Frequencies

GnomAD3 genomes

AF:

0.724

AC:

109257

AN:

150818

Hom.:

39988

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.869

Gnomad AMR

AF:

0.648

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.739

Gnomad SAS

AF:

0.704

Gnomad FIN

AF:

0.770

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.792

Gnomad OTH

AF:

0.702

GnomAD2 exomes

AF:

0.711

AC:

140999

AN:

198208

AF XY:

0.718

show subpopulations

Gnomad AFR exome

AF:

0.598

Gnomad AMR exome

AF:

0.579

Gnomad ASJ exome

AF:

0.711

Gnomad EAS exome

AF:

0.707

Gnomad FIN exome

AF:

0.770

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.706

GnomAD4 exome

AF:

0.811

AC:

1040736

AN:

1283558

Hom.:

440365

Cov.:

AF XY:

0.808

AC XY:

518094

AN XY:

640838

show subpopulations

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

African (AFR)

AF:

0.627

AC:

18748

AN:

29914

American (AMR)

AF:

0.625

AC:

24915

AN:

39856

Ashkenazi Jewish (ASJ)

AF:

0.722

AC:

17517

AN:

24268

East Asian (EAS)

AF:

0.765

AC:

28947

AN:

37848

South Asian (SAS)

AF:

0.740

AC:

59325

AN:

80180

European-Finnish (FIN)

AF:

0.766

AC:

39329

AN:

51346

Middle Eastern (MID)

AF:

0.666

AC:

3382

AN:

5080

European-Non Finnish (NFE)

AF:

0.839

AC:

806519

AN:

960830

Other (OTH)

AF:

0.775

AC:

42054

AN:

54236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.379

Heterozygous variant carriers

7514

15029

22543

30058

37572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16872

33744

50616

67488

84360

<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:

0.724

AC:

109308

AN:

150936

Hom.:

39999

Cov.:

AF XY:

0.719

AC XY:

52971

AN XY:

73652

show subpopulations

African (AFR)

AF:

0.630

AC:

25911

AN:

41098

American (AMR)

AF:

0.647

AC:

9834

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.710

AC:

2449

AN:

3450

East Asian (EAS)

AF:

0.738

AC:

3735

AN:

5060

South Asian (SAS)

AF:

0.705

AC:

3352

AN:

4756

European-Finnish (FIN)

AF:

0.770

AC:

8062

AN:

10464

Middle Eastern (MID)

AF:

0.670

AC:

197

AN:

294

European-Non Finnish (NFE)

AF:

0.792

AC:

53524

AN:

67620

Other (OTH)

AF:

0.697

AC:

1455

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

1328

2656

3983

5311

6639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.690

Hom.:

3793

Bravo

AF:

0.719

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Interstitial lung disease 2 (1)

SFTPA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

-1.3

PromoterAI

-0.047

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.71

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.63

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over