4-99345478-A-G

Variant names:

• chr4-99345478-A-G
• rs1662052
• NM_000669.5:c.260-212T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000669.5(ADH1C):​c.260-212T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 152,166 control chromosomes in the GnomAD database, including 8,851 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 0.31 (8851 hom., cov: 33)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.853
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	NM_000669.5	MANE Select	c.260-212T>C		intron	N/A	NP_000660.1
	ADH1C	NR_133005.2		n.331-212T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.260-212T>C		intron	N/A	ENSP00000426083.1
	ADH1C	ENST00000510055.5	TSL:3	c.140-212T>C		intron	N/A	ENSP00000478439.1
	ADH1C	ENST00000511397.3	TSL:3	c.158-212T>C		intron	N/A	ENSP00000478545.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47467 AN: 152048 Hom.: 8845 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0815

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.279

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.312 AC: 47488 AN: 152166 Hom.: 8851 Cov.: 33 AF XY: 0.313 AC XY: 23248 AN XY: 74374

African (AFR) AF: 0.144 AC: 5964 AN: 41542

American (AMR) AF: 0.292 AC: 4465 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3470

East Asian (EAS) AF: 0.0811 AC: 421 AN: 5190

South Asian (SAS) AF: 0.296 AC: 1430 AN: 4830

European-Finnish (FIN) AF: 0.512 AC: 5405 AN: 10550

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.412 AC: 27986 AN: 67974

Other (OTH) AF: 0.282 AC: 596 AN: 2116

Alfa AF: 0.364 Hom.: 1477

Bravo AF: 0.287

Asia WGS AF: 0.220 AC: 762 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		-0.85

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: rs1662052; hg19: chr4-100266635;