4-99345173-A-G

Variant names:

• chr4-99345173-A-G
• rs1693426
• NM_000669.5:c.347+6T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_000669.5(ADH1C):​c.347+6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.38 in 1,611,602 control chromosomes in the GnomAD database, including 124,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8854 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115555 hom.)
• Consequence: ADH1C NM_000669.5 splice_region, intron
• Scores: Splicing: ADA: 0.9660
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• Publications: 12 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 -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.347+6T>C		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.418+6T>C		splice_region_variant, intron_variant	Intron 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.347+6T>C		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.227+6T>C		splice_region_variant, intron_variant	Intron 5 of 6	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.245+6T>C		splice_region_variant, intron_variant	Intron 3 of 4	3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.370+6T>C		splice_region_variant, intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47472 AN: 151998 Hom.: 8848 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0814

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.343 AC: 85445 AN: 248982 AF XY: 0.347

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.0774

Gnomad FIN exome AF: 0.516

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.388 AC: 565694 AN: 1459486 Hom.: 115555 Cov.: 39 AF XY: 0.384 AC XY: 279111 AN XY: 725994

African (AFR) AF: 0.134 AC: 4474 AN: 33458

American (AMR) AF: 0.322 AC: 14319 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7127 AN: 26118

East Asian (EAS) AF: 0.0648 AC: 2573 AN: 39688

South Asian (SAS) AF: 0.321 AC: 27652 AN: 86132

European-Finnish (FIN) AF: 0.515 AC: 27451 AN: 53346

Middle Eastern (MID) AF: 0.269 AC: 1550 AN: 5764

European-Non Finnish (NFE) AF: 0.413 AC: 458888 AN: 1110134

Other (OTH) AF: 0.359 AC: 21660 AN: 60314

GnomAD4 genome AF: 0.312 AC: 47493 AN: 152116 Hom.: 8854 Cov.: 33 AF XY: 0.313 AC XY: 23246 AN XY: 74344

African (AFR) AF: 0.144 AC: 5967 AN: 41518

American (AMR) AF: 0.292 AC: 4465 AN: 15284

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

East Asian (EAS) AF: 0.0810 AC: 420 AN: 5186

South Asian (SAS) AF: 0.295 AC: 1423 AN: 4818

European-Finnish (FIN) AF: 0.513 AC: 5414 AN: 10550

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27989 AN: 67974

Other (OTH) AF: 0.282 AC: 594 AN: 2110

Alfa AF: 0.359 Hom.: 4683

Bravo AF: 0.287

Asia WGS AF: 0.220 AC: 764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	21
DANN	Benign	0.69
PhyloP100		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.010		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: rs1693426; hg19: chr4-100266330; COSMIC: COSV72463470;