chr10-79559336-C-T

Variant names:

• chr10-79559336-C-T
• rs192907309
• NM_001098668.4:c.148G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320814.1(SFTPA2):​c.178G>A​(p.Val60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V60L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SFTPA2 NM_001320814.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089821994).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320814.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA2	NM_001098668.4	MANE Select	c.148G>A	p.Val50Ile	missense	Exon 3 of 6	NP_001092138.1
	SFTPA2	NM_001320814.1		c.178G>A	p.Val60Ile	missense	Exon 2 of 5	NP_001307743.1
	SFTPA2	NM_001320813.2		c.148G>A	p.Val50Ile	missense	Exon 3 of 6	NP_001307742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.148G>A	p.Val50Ile	missense	Exon 3 of 6	ENSP00000361400.2
	SFTPA2	ENST00000372327.9	TSL:1	c.148G>A	p.Val50Ile	missense	Exon 2 of 5	ENSP00000361402.5
	SFTPA2	ENST00000959071.1		c.148G>A	p.Val50Ile	missense	Exon 3 of 6	ENSP00000629130.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.93e-7 AC: 1 AN: 1443698 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718688

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

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095160

Other (OTH) AF: 0.00 AC: 0 AN: 59836

⚠️ 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.

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.026
DANN	Benign	0.76
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.87	T
PhyloP100		-1.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.022
Sift	Benign	0.50	T
Sift4G	Benign	0.49	T
Vest4		0.070
MutPred		0.37		Loss of methylation at R47 (P = 0.0849)
MVP		0.33
MPC		1.0
ClinPred		0.028	T
GERP RS		-4.2
PromoterAI		-0.010	Neutral
gMVP		0.080
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192907309; hg19: chr10-81319092;