Genetic Variant ASIC5:p.Ala435Val (chr4-155831847-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017419.3(ASIC5):c.1304C>T(p.Ala435Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000567 in 1,604,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ASIC5
NM_017419.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

Variant links:

Genes affected

ASIC5 (HGNC:17537): (acid sensing ion channel subunit family member 5) This gene belongs to the amiloride-sensitive Na+ channel and degenerin (NaC/DEG) family, members of which have been identified in many animal species ranging from the nematode to human. The amiloride-sensitive Na(+) channel encoded by this gene is primarily expressed in the small intestine, however, its exact function is not known. [provided by RefSeq, Jul 2008]

ASIC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASIC5	NM_017419.3 link	c.1304C>T	p.Ala435Val	missense_variant	Exon 9 of 10	ENST00000537611.3	NP_059115.1	Q9NY37
ASIC5	XM_017008291.2 link	c.1178C>T	p.Ala393Val	missense_variant	Exon 8 of 9		XP_016863780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASIC5	ENST00000537611.3 link	c.1304C>T	p.Ala435Val	missense_variant	Exon 9 of 10	1	NM_017419.3	ENSP00000442477.2		Q9NY37

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000800

AC:

AN:

249994

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.000744

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1452272

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

723172

show subpopulations

Gnomad4 AFR exome

AF:

0.000843

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000761

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000906

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.000276

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.000894

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000865

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1304C>T (p.A435V) alteration is located in exon 9 (coding exon 9) of the ASIC5 gene. This alteration results from a C to T substitution at nucleotide position 1304, causing the alanine (A) at amino acid position 435 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

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.44

Sift

Uncertain

0.015

Sift4G

Uncertain

0.011

Polyphen

0.97

Vest4

0.71

MVP

0.31

MPC

0.077

ClinPred

0.32

GERP RS

3.8

Varity_R

0.34

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over