4-99342956-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000669.5(ADH1C):​c.667G>A​(p.Val223Met) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ADH1C
NM_000669.5 missense

Scores

1
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97
Variant links:
Genes affected
ADH1C (HGNC:251): (alcohol dehydrogenase 1C (class I), gamma polypeptide) This gene encodes class I alcohol dehydrogenase, gamma subunit, which is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class I alcohol dehydrogenase, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation to acetaldehyde, thus playing a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. An association between ADH1C polymorphism and alcohol dependence has not been established. [provided by RefSeq, Sep 2019]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4064101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADH1CNM_000669.5 linkc.667G>A p.Val223Met missense_variant Exon 6 of 9 ENST00000515683.6 NP_000660.1 P00326
ADH1CNR_133005.2 linkn.738G>A non_coding_transcript_exon_variant Exon 6 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADH1CENST00000515683.6 linkc.667G>A p.Val223Met missense_variant Exon 6 of 9 1 NM_000669.5 ENSP00000426083.1 P00326
ADH1CENST00000510055.5 linkc.547G>A p.Val183Met missense_variant Exon 7 of 7 3 ENSP00000478439.1 A0A087WU81
ADH1CENST00000511397.3 linkc.*55G>A downstream_gene_variant 3 ENSP00000478545.1 A0A087WUC4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.667G>A (p.V223M) alteration is located in exon 6 (coding exon 6) of the ADH1C gene. This alteration results from a G to A substitution at nucleotide position 667, causing the valine (V) at amino acid position 223 to be replaced by a methionine (M). 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
0.46
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.036
T;T
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.84
T;T
MetaRNN
Benign
0.41
T;T
MutationAssessor
Uncertain
2.8
M;.
PrimateAI
Benign
0.44
T
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.64
MVP
0.20
GERP RS
2.3
Varity_R
0.40
gMVP
0.66

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: chr4-100264113; API