7-151049017-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004769.4(ASIC3):​c.132G>A​(p.Met44Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ASIC3
NM_004769.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.163
Variant links:
Genes affected
ASIC3 (HGNC:101): (acid sensing ion channel subunit 3) This gene encodes a member of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, two hydrophobic transmembrane regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The member encoded by this gene is an acid sensor and may play an important role in the detection of lasting pH changes. In addition, a heteromeric association between this member and acid-sensing (proton-gated) ion channel 2 has been observed as proton-gated channels sensitive to gadolinium. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18292862).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASIC3NM_004769.4 linkc.132G>A p.Met44Ile missense_variant Exon 1 of 11 ENST00000349064.10 NP_004760.1 Q9UHC3-1A0A090N7X8
ASIC3NM_020321.3 linkc.132G>A p.Met44Ile missense_variant Exon 1 of 11 NP_064717.1 Q9UHC3-3A0A090N8Q1
ASIC3NM_020322.3 linkc.132G>A p.Met44Ile missense_variant Exon 1 of 10 NP_064718.1 Q9UHC3-2A0A090N8Z6
ASIC3NR_046401.1 linkn.726G>A non_coding_transcript_exon_variant Exon 1 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASIC3ENST00000349064.10 linkc.132G>A p.Met44Ile missense_variant Exon 1 of 11 1 NM_004769.4 ENSP00000344838.5 Q9UHC3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000520
AC:
13
AN:
249938
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135248
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000377
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1460394
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726552
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000268
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000453
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 07, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.132G>A (p.M44I) alteration is located in exon 1 (coding exon 1) of the ASIC3 gene. This alteration results from a G to A substitution at nucleotide position 132, causing the methionine (M) at amino acid position 44 to be replaced by an isoleucine (I). 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
0.14
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
11
DANN
Benign
0.96
DEOGEN2
Benign
0.11
.;T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.33
N
LIST_S2
Benign
0.84
T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.61
N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.040
N;N;N
REVEL
Benign
0.13
Sift
Benign
0.067
T;T;T
Sift4G
Uncertain
0.050
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.24
MutPred
0.77
Loss of MoRF binding (P = 0.0848);Loss of MoRF binding (P = 0.0848);Loss of MoRF binding (P = 0.0848);
MVP
0.45
MPC
0.10
ClinPred
0.036
T
GERP RS
-0.51
Varity_R
0.15
gMVP
0.28

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.

Other links and lift over

dbSNP: rs754949155; hg19: chr7-150746104; API