chr4-99342789-T-A

Variant names:

• chr4-99342789-T-A
• rs553651224
• NM_000669.5:c.828+6A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000669.5(ADH1C):​c.828+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,610,308 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (9 hom.)
• Consequence: ADH1C NM_000669.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001616
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.15
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 4-99342789-T-A is Benign according to our data. Variant chr4-99342789-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2654965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.828+6A>T		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.855+50A>T		intron_variant	Intron 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.828+6A>T		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.*137A>T		downstream_gene_variant		3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.*222A>T		downstream_gene_variant		3		ENSP00000478545.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 250496 AF XY: 0.00134

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00218 AC: 3182 AN: 1457986 Hom.: 9 Cov.: 71 AF XY: 0.00215 AC XY: 1556 AN XY: 725402

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000269 AC: 9 AN: 33470

American (AMR) AF: 0.00123 AC: 55 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00441 AC: 115 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86208

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00249 AC: 2761 AN: 1108392

Other (OTH) AF: 0.00234 AC: 141 AN: 60278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74476

African (AFR) AF: 0.000385 AC: 16 AN: 41592

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00380 Hom.: 0

Bravo AF: 0.00230

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADH1C: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.020
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: rs553651224; hg19: chr4-100263946;