chr4-99347699-A-C

Position:

• chr4-99347699-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000669.5(ADH1C):​c.120+46T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,517,206 control chromosomes in the GnomAD database, including 66,912 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4908 hom., cov: 33)
  • Exomes 𝑓: 0.29 (62004 hom.)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104

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]

ADH1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.120+46T>G		intron_variant		ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.191+46T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.120+46T>G		intron_variant		1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.-1+46T>G		intron_variant		3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.19-555T>G		intron_variant		3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.189+46T>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35422 AN: 152072 Hom.: 4905 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.255 AC: 51246 AN: 201272 Hom.: 7427 AF XY: 0.259 AC XY: 28439 AN XY: 109676

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0227

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.292 AC: 398417 AN: 1365016 Hom.: 62004 Cov.: 24 AF XY: 0.290 AC XY: 195914 AN XY: 676538

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.374

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.233 AC: 35433 AN: 152190 Hom.: 4908 Cov.: 33 AF XY: 0.231 AC XY: 17185 AN XY: 74396

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.206

Alfa AF: 0.236 Hom.: 1564

Bravo AF: 0.213

Asia WGS AF: 0.114 AC: 394 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.3
DANN	Benign	0.65

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

LitVar

Other links and lift over

dbSNP: rs1789920; hg19: chr4-100268856;