10-79559511-C-A

Variant names:

• chr10-79559511-C-A
• rs1650232
• NM_001098668.4:c.-23-5G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001098668.4(SFTPA2):​c.-23-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 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_001098668.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002446
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.31
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA2	NM_001098668.4	c.-23-5G>T		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000372325.7	NP_001092138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA2	ENST00000372325.7	c.-23-5G>T		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_001098668.4	ENSP00000361400.2

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1751 AN: 151246 Hom.: 34 Cov.: 28

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

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.: 27 Cov.: 55 AF XY: 0.00147 AC XY: 1046 AN XY: 713470

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: 0 AN: 25848

East Asian (EAS) AF: 0.00216 AC: 85 AN: 39378

South Asian (SAS) AF: 0.000586 AC: 50 AN: 85294

European-Finnish (FIN) AF: 0.000284 AC: 15 AN: 52904

Middle Eastern (MID) AF: 0.00549 AC: 30 AN: 5466

European-Non Finnish (NFE) AF: 0.000511 AC: 557 AN: 1089908

Other (OTH) AF: 0.00374 AC: 222 AN: 59354

GnomAD4 genome AF: 0.0116 AC: 1759 AN: 151366 Hom.: 34 Cov.: 28 AF XY: 0.0110 AC XY: 809 AN XY: 73874

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: 0 AN: 3458

East Asian (EAS) AF: 0.00237 AC: 12 AN: 5072

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4770

European-Finnish (FIN) AF: 0.000286 AC: 3 AN: 10498

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000708 AC: 48 AN: 67784

Other (OTH) AF: 0.0110 AC: 23 AN: 2096

Alfa AF: 0.000703 Hom.: 3793

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SFTPA2-related disorder Benign:1

Mar 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.19
DANN	Benign	0.49
PhyloP100		-1.3
PromoterAI		-0.073	Neutral
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1650232; hg19: chr10-81319267;