chr4-99345058-A-G

Variant names:

• chr4-99345058-A-G
• rs1192195322
• NM_000669.5:c.371T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

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_000669.5. 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
	ADH1C	NM_000669.5	MANE Select	c.371T>C	p.Leu124Pro	missense	Exon 5 of 9	NP_000660.1	P00326
	ADH1C	NR_133005.2		n.442T>C		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.371T>C	p.Leu124Pro	missense	Exon 5 of 9	ENSP00000426083.1	P00326
	ADH1C	ENST00000865215.1		c.371T>C	p.Leu124Pro	missense	Exon 6 of 10	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.371T>C	p.Leu124Pro	missense	Exon 6 of 10	ENSP00000535275.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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	0.79
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T
MetaRNN	Uncertain	0.71	D
MutationAssessor	Benign	0.37	N
PhyloP100		6.7
PrimateAI	Benign	0.44	T
Sift4G	Pathogenic	0.0	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

Other links and lift over

dbSNP: rs1192195322; hg19: chr4-100266215;