4-99339632-T-C

Variant names:

• chr4-99339632-T-C
• rs698
• NM_000669.5:c.1048A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000669.5(ADH1C):​c.1048A>G​(p.Ile350Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,609,470 control chromosomes in the GnomAD database, including 124,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (8849 hom., cov: 31)
  • Exomes 𝑓: 0.39 (115576 hom.)
• Consequence: ADH1C NM_000669.5 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 3.58
• Publications: 182 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5579672E-4).
• BP6: Variant 4-99339632-T-C is Benign according to our data. Variant chr4-99339632-T-C is described in ClinVar as [protective]. Clinvar id is 18180.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.1048A>G	p.Ile350Val	missense_variant	Exon 8 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.1075A>G		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.1048A>G	p.Ile350Val	missense_variant	Exon 8 of 9	1	NM_000669.5	ENSP00000426083.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47433 AN: 151572 Hom.: 8842 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.346 AC: 85871 AN: 248348 AF XY: 0.349

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.0781

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.388 AC: 565349 AN: 1457778 Hom.: 115576 Cov.: 32 AF XY: 0.385 AC XY: 278988 AN XY: 725162

African (AFR) AF: 0.134 AC: 4447 AN: 33272

American (AMR) AF: 0.321 AC: 14190 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7118 AN: 26064

East Asian (EAS) AF: 0.0649 AC: 2571 AN: 39618

South Asian (SAS) AF: 0.321 AC: 27470 AN: 85538

European-Finnish (FIN) AF: 0.515 AC: 27434 AN: 53266

Middle Eastern (MID) AF: 0.268 AC: 1544 AN: 5756

European-Non Finnish (NFE) AF: 0.413 AC: 458920 AN: 1109848

Other (OTH) AF: 0.359 AC: 21655 AN: 60262

GnomAD4 genome AF: 0.313 AC: 47454 AN: 151692 Hom.: 8849 Cov.: 31 AF XY: 0.314 AC XY: 23229 AN XY: 74064

African (AFR) AF: 0.144 AC: 5945 AN: 41328

American (AMR) AF: 0.293 AC: 4460 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3472

East Asian (EAS) AF: 0.0816 AC: 420 AN: 5144

South Asian (SAS) AF: 0.295 AC: 1419 AN: 4810

European-Finnish (FIN) AF: 0.516 AC: 5416 AN: 10506

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

European-Non Finnish (NFE) AF: 0.412 AC: 27975 AN: 67920

Other (OTH) AF: 0.283 AC: 596 AN: 2106

Alfa AF: 0.353 Hom.: 29066

Bravo AF: 0.287

TwinsUK AF: 0.410 AC: 1521

ALSPAC AF: 0.398 AC: 1532

ESP6500AA AF: 0.152 AC: 659

ESP6500EA AF: 0.386 AC: 3319

ExAC AF: 0.343 AC: 41620

Asia WGS AF: 0.221 AC: 765 AN: 3478

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Alcohol dependence Benign:1

Jun 01, 2008

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.69
DEOGEN2	Benign	0.0078	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.00046	T
MutationAssessor	Benign	-1.8	N
PhyloP100		3.6
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.014
GERP RS		3.9
Varity_R		0.024
gMVP		0.40

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: rs698; hg19: chr4-100260789; COSMIC: COSV72624794; COSMIC: COSV72624794;