10-79557468-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001098668.4(SFTPA2):c.488C>T(p.Ala163Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain C-type lectin (size 116) in uniprot entity SFPA2_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) in NM_001098668.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA2	NM_001098668.4	c.488C>T	p.Ala163Val	missense_variant	6/6	ENST00000372325.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA2	ENST00000372325.7	c.488C>T	p.Ala163Val	missense_variant	6/6	1	NM_001098668.4	P1
SFTPA2	ENST00000372327.9	c.488C>T	p.Ala163Val	missense_variant	5/5	1		P1
SFTPA2	ENST00000417041.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250364 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461556 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.488C>T (p.A163V) alteration is located in exon 6 (coding exon 4) of the SFTPA2 gene. This alteration results from a C to T substitution at nucleotide position 488, causing the alanine (A) at amino acid position 163 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.0032	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;D
Vest4		0.70
MutPred		0.68		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.50
MPC		2.2
ClinPred		0.97	D
GERP RS		3.0
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs778933336; hg19: chr10-81317224;