4-99344993-T-A

Position:

• chr4-99344993-T-A

Variant summary

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

The ENST00000515683.6(ADH1C):​c.436A>T​(p.Thr146Ser) 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 ENST00000515683.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.436A>T	p.Thr146Ser	missense_variant	5/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.507A>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.436A>T	p.Thr146Ser	missense_variant	5/9	1	NM_000669.5	ENSP00000426083	P1
ADH1C	ENST00000510055.5	c.316A>T	p.Thr106Ser	missense_variant	6/7	3		ENSP00000478439
ADH1C	ENST00000511397.3	c.334A>T	p.Thr112Ser	missense_variant	4/5	3		ENSP00000478545
ADH1C	ENST00000505942.2	n.459A>T		non_coding_transcript_exon_variant	5/5	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.436A>T (p.T146S) alteration is located in exon 5 (coding exon 5) of the ADH1C gene. This alteration results from a A to T substitution at nucleotide position 436, causing the threonine (T) at amino acid position 146 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.030	T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Uncertain	0.46	T;T;T
MutationAssessor	Benign	0.86	L;.;.
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.055	T;.;T
Polyphen		0.0020	B;.;.
Vest4		0.20
MVP		0.51
GERP RS		2.9
Varity_R		0.10
gMVP		0.44

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: chr4-100266150;