4-99342945-G-A

Variant names:

• chr4-99342945-G-A
• rs6413444
• NM_000669.5:c.678C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000669.5(ADH1C):​c.678C>T​(p.Asn226Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,132 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.015 (195 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84
• Publications: 6 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-99342945-G-A is Benign according to our data. Variant chr4-99342945-G-A is described in ClinVar as [Benign]. Clinvar id is 2654966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0145 (21234/1461880) while in subpopulation NFE AF = 0.0156 (17308/1112008). AF 95% confidence interval is 0.0154. There are 195 homozygotes in GnomAdExome4. There are 10443 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.678C>T	p.Asn226Asn	synonymous_variant	Exon 6 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.749C>T		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.678C>T	p.Asn226Asn	synonymous_variant	Exon 6 of 9	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.558C>T	p.Asn186Asn	synonymous_variant	Exon 7 of 7	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.*66C>T		downstream_gene_variant		3		ENSP00000478545.1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152134 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0118 AC: 2970 AN: 251460 AF XY: 0.0123

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0145 AC: 21234 AN: 1461880 Hom.: 195 Cov.: 33 AF XY: 0.0144 AC XY: 10443 AN XY: 727242

African (AFR) AF: 0.00206 AC: 69 AN: 33478

American (AMR) AF: 0.00749 AC: 335 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 652 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0104 AC: 897 AN: 86258

European-Finnish (FIN) AF: 0.0202 AC: 1080 AN: 53420

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0156 AC: 17308 AN: 1112008

Other (OTH) AF: 0.0142 AC: 859 AN: 60390

GnomAD4 genome AF: 0.0102 AC: 1555 AN: 152252 Hom.: 14 Cov.: 32 AF XY: 0.0104 AC XY: 771 AN XY: 74436

African (AFR) AF: 0.00296 AC: 123 AN: 41556

American (AMR) AF: 0.00707 AC: 108 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4816

European-Finnish (FIN) AF: 0.0205 AC: 217 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 956 AN: 68030

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0136 Hom.: 6

Bravo AF: 0.00889

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADH1C: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.6
DANN	Benign	0.52
PhyloP100		1.8

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: rs6413444; hg19: chr4-100264102;