4-155863515-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017419.3(ASIC5):c.280A>G(p.Thr94Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000293 in 1,613,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

ASIC5
NM_017419.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

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:

LOC105377507 (HGNC:):

LOC105377507 links:

TDO2 (HGNC:11708): (tryptophan 2,3-dioxygenase) This gene encodes a heme enzyme that plays a critical role in tryptophan metabolism by catalyzing the first and rate-limiting step of the kynurenine pathway. Increased activity of the encoded protein and subsequent kynurenine production may also play a role in cancer through the suppression of antitumor immune responses, and single nucleotide polymorphisms in this gene may be associated with autism. [provided by RefSeq, Feb 2012]

TDO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ASIC5	NM_017419.3 linkuse as main transcript	c.280A>G	p.Thr94Ala	missense_variant	2/10	ENST00000537611.3
LOC105377507	XR_001741901.2 linkuse as main transcript	n.211+4617T>C		intron_variant, non_coding_transcript_variant
ASIC5	XM_017008291.2 linkuse as main transcript	c.280A>G	p.Thr94Ala	missense_variant	2/9
LOC105377507	XR_939389.3 linkuse as main transcript	n.4828T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASIC5	ENST00000537611.3 linkuse as main transcript	c.280A>G	p.Thr94Ala	missense_variant	2/10	1	NM_017419.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000837

AC:

AN:

250894

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135578

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000309

AC:

451

AN:

1461488

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

205

AN XY:

727014

show subpopulations

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:

0.0000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000377

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000145

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.280A>G (p.T94A) alteration is located in exon 2 (coding exon 2) of the ASIC5 gene. This alteration results from a A to G substitution at nucleotide position 280, causing the threonine (T) at amino acid position 94 to be replaced by an alanine (A). 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

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.16

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.70

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

0.58

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.43

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.025

Polyphen

0.77

Vest4

0.75

MVP

0.76

MPC

0.086

ClinPred

0.61

GERP RS

4.3

Varity_R

0.29

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

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

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