4-99344907-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000669.5(ADH1C):c.522C>T(p.Gly174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0061 in 1,614,160 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (43 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.931

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 4-99344907-G-A is Benign according to our data. Variant chr4-99344907-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 776589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.931 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1C	NM_000669.5	c.522C>T	p.Gly174=	synonymous_variant	5/9	ENST00000515683.6
ADH1C	NR_133005.2	n.593C>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1C	ENST00000515683.6	c.522C>T	p.Gly174=	synonymous_variant	5/9	1	NM_000669.5	P1
ADH1C	ENST00000510055.5	c.402C>T	p.Gly134=	synonymous_variant	6/7	3
ADH1C	ENST00000511397.3	c.420C>T	p.Gly140=	synonymous_variant	4/5	3
ADH1C	ENST00000505942.2	n.545C>T		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00462 AC: 1163 AN: 251464 Hom.: 7 AF XY: 0.00501 AC XY: 681 AN XY: 135908

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00633 AC: 9261 AN: 1461882 Hom.: 43 Cov.: 31 AF XY: 0.00631 AC XY: 4591 AN XY: 727240

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00721

Gnomad4 OTH exome AF: 0.00710

GnomAD4 genome AF: 0.00385 AC: 587 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.00393 AC XY: 293 AN XY: 74468

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00519 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	ADH1C: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Apr 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.2
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55717907; hg19: chr4-100266064;