dbSNP rs1650232: SFTPA2:c.-23-5G>T (chr10-79559511-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_StrongBP6BS1BS2

The NM_001320813.2(SFTPA2):c.-26-2G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,585,742 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.012 ( 34 hom., cov: 28)

Exomes 𝑓: 0.0016 ( 27 hom. )

Consequence

SFTPA2
NM_001320813.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.00002446

Clinical Significance

Likely benign no assertion criteria provided B:1

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 Submitted by: PanelApp Australia, ClinGen
interstitial lung disease 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
idiopathic pulmonary fibrosis
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine

SFTPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 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 10, offset of 3, new splice context is: cacggccatccctcctgcAGgag. 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-A is Benign according to our data. Variant chr10-79559511-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3060374.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1759/151366) while in subpopulation AFR AF = 0.0381 (1569/41230). AF 95% confidence interval is 0.0365. There are 34 homozygotes in GnomAd4. There are 809 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAd4 at 1759 AD,Unknown gene.

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	UniProt
SFTPA2	NM_001098668.4	MANE Select	c.-23-5G>T	splice_region intron	N/A	NP_001092138.1	Q8IWL1
SFTPA2	NM_001320814.1		c.8-5G>T	splice_region intron	N/A	NP_001307743.1
SFTPA2	NM_001320813.2		c.-26-2G>T	splice_acceptor intron	N/A	NP_001307742.1	Q8IWL1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.-23-5G>T	splice_region intron	N/A	ENSP00000361400.2	Q8IWL1
SFTPA2	ENST00000372327.9	TSL:1	c.-23-5G>T	splice_region intron	N/A	ENSP00000361402.5	Q8IWL1
SFTPA2	ENST00000640627.1	TSL:1	c.23-5G>T	splice_region intron	N/A	ENSP00000492537.1	A0A1W2PR89

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1751

AN:

151246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0380

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00236

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000286

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000708

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00363

AC:

719

AN:

198208

AF XY:

0.00275

show subpopulations

Gnomad AFR exome

AF:

0.0392

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00253

Gnomad FIN exome

AF:

0.0000600

Gnomad NFE exome

AF:

0.000562

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00163

AC:

2341

AN:

1434376

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1046

AN XY:

713470

show subpopulations

African (AFR)

AF:

0.0388

AC:

1277

AN:

32942

American (AMR)

AF:

0.00243

AC:

105

AN:

43282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25848

East Asian (EAS)

AF:

0.00216

AC:

AN:

39378

South Asian (SAS)

AF:

0.000586

AC:

AN:

85294

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

52904

Middle Eastern (MID)

AF:

0.00549

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.000511

AC:

557

AN:

1089908

Other (OTH)

AF:

0.00374

AC:

222

AN:

59354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0116

AC:

1759

AN:

151366

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

809

AN XY:

73874

show subpopulations

African (AFR)

AF:

0.0381

AC:

1569

AN:

41230

American (AMR)

AF:

0.00662

AC:

101

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00237

AC:

AN:

5072

South Asian (SAS)

AF:

0.000419

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.000286

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000708

AC:

AN:

67784

Other (OTH)

AF:

0.0110

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000703

Hom.:

3793

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

SFTPA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.19

(source)

DANN

Benign

0.49

PhyloP100

-1.3

PromoterAI

-0.073

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over