NM_004769.4:c.74C>T

Variant names:

• chr7-151048959-C-T
• rs766347273
• NM_004769.4:c.74C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004769.4(ASIC3):​c.74C>T​(p.Ser25Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000125 in 1,595,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S25A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ASIC3 NM_004769.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004769.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIC3	NM_004769.4	MANE Select	c.74C>T	p.Ser25Leu	missense	Exon 1 of 11	NP_004760.1	Q9UHC3-1
	ASIC3	NM_020321.3		c.74C>T	p.Ser25Leu	missense	Exon 1 of 11	NP_064717.1	Q9UHC3-3
	ASIC3	NM_020322.3		c.74C>T	p.Ser25Leu	missense	Exon 1 of 10	NP_064718.1	Q9UHC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIC3	ENST00000349064.10	TSL:1 MANE Select	c.74C>T	p.Ser25Leu	missense	Exon 1 of 11	ENSP00000344838.5	Q9UHC3-1
	ASIC3	ENST00000297512.12	TSL:1	c.74C>T	p.Ser25Leu	missense	Exon 1 of 11	ENSP00000297512.8	Q9UHC3-3
	ASIC3	ENST00000357922.8	TSL:1	c.74C>T	p.Ser25Leu	missense	Exon 1 of 10	ENSP00000350600.4	Q9UHC3-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 4 AN: 242870 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1443592 Hom.: 0 Cov.: 31 AF XY: 0.0000126 AC XY: 9 AN XY: 715024

African (AFR) AF: 0.00 AC: 0 AN: 33146

American (AMR) AF: 0.0000454 AC: 2 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39282

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000910 AC: 10 AN: 1099278

Other (OTH) AF: 0.00 AC: 0 AN: 59510

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

African (AFR) AF: 0.0000965 AC: 4 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.012
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.56	P
Vest4		0.33
MutPred		0.81		Loss of disorder (P = 0.0373)
MVP		0.73
MPC		0.12
ClinPred		0.69	D
GERP RS		5.0
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.37
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs766347273; hg19: chr7-150746046; COSMIC: COSV99874923; COSMIC: COSV99874923;