7-151049010-G-C

Variant names:

• chr7-151049010-G-C
• NM_004769.4:c.125G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004769.4(ASIC3):​c.125G>C​(p.Arg42Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASIC3 NM_004769.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASIC3	NM_004769.4	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 11	ENST00000349064.10	NP_004760.1
ASIC3	NM_020321.3	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 11		NP_064717.1
ASIC3	NM_020322.3	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 10		NP_064718.1
ASIC3	NR_046401.1	n.719G>C		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASIC3	ENST00000349064.10	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 11	1	NM_004769.4	ENSP00000344838.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125G>C (p.R42P) alteration is located in exon 1 (coding exon 1) of the ASIC3 gene. This alteration results from a G to C substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a proline (P). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.50
MutPred		0.89		Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);
MVP		0.83
MPC		0.58
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-150746097;