4-99342945-G-T

Variant names:

• chr4-99342945-G-T
• rs6413444
• NM_000669.5:c.678C>A

Variant summary

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

The NM_000669.5(ADH1C):​c.678C>A​(p.Asn226Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N226N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH1C NM_000669.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 6 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.678C>A	p.Asn226Lys	missense_variant	Exon 6 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.749C>A		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.678C>A	p.Asn226Lys	missense_variant	Exon 6 of 9	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.558C>A	p.Asn186Lys	missense_variant	Exon 7 of 7	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.*66C>A		downstream_gene_variant		3		ENSP00000478545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Uncertain	0.72	D;D
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		1.8
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.45
GERP RS		4.0
Varity_R		0.51
gMVP		0.63

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: rs6413444; hg19: chr4-100264102;