NM_000668.6:c.665C>A

Variant names:

• chr4-99313984-G-T
• NM_000668.6:c.665C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000668.6(ADH1B):​c.665C>A​(p.Ala222Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.563

Genes affected

ADH1B (HGNC:250): (alcohol dehydrogenase 1B (class I), beta polypeptide) The protein encoded by this gene 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. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1B	NM_000668.6	c.665C>A	p.Ala222Glu	missense_variant	Exon 6 of 9	ENST00000305046.13	NP_000659.2
ADH1B	NM_001286650.2	c.545C>A	p.Ala182Glu	missense_variant	Exon 7 of 10		NP_001273579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1B	ENST00000305046.13	c.665C>A	p.Ala222Glu	missense_variant	Exon 6 of 9	1	NM_000668.6	ENSP00000306606.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T;T;.
Eigen	Benign	0.056
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.78	.;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.65	T
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Vest4		0.71
MutPred		0.86		Loss of MoRF binding (P = 0.0684);.;.;Loss of MoRF binding (P = 0.0684);
MVP		0.36
MPC		0.72
ClinPred		0.99	D
GERP RS		-0.18
gMVP		0.92

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: chr4-100235141;