NM_000669.5:c.371T>C

Variant names:

• chr4-99345058-A-G
• NM_000669.5:c.371T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000669.5(ADH1C):​c.371T>C​(p.Leu124Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADH1C NM_000669.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.371T>C	p.Leu124Pro	missense_variant	Exon 5 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.442T>C		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.371T>C	p.Leu124Pro	missense_variant	Exon 5 of 9	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.251T>C	p.Leu84Pro	missense_variant	Exon 6 of 7	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.269T>C	p.Leu90Pro	missense_variant	Exon 4 of 5	3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.394T>C		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371T>C (p.L124P) alteration is located in exon 5 (coding exon 5) of the ADH1C gene. This alteration results from a T to C substitution at nucleotide position 371, causing the leucine (L) at amino acid position 124 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Uncertain	0.71	D;D;D
MutationAssessor	Benign	0.37	N;.;.
PrimateAI	Benign	0.44	T
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.36
MVP		0.41
GERP RS		4.1
Varity_R		0.58
gMVP		0.69

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: chr4-100266215;