chr4-99339626-G-T

Position:

• chr4-99339626-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000669.5(ADH1C):​c.1054C>A​(p.Pro352Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,606,172 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (81 hom.)
• Consequence: ADH1C NM_000669.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046266615).
• BP6: Variant 4-99339626-G-T is Benign according to our data. Variant chr4-99339626-G-T is described in ClinVar as [Benign]. Clinvar id is 778860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00525 (796/151720) while in subpopulation AMR AF= 0.0311 (472/15190). AF 95% confidence interval is 0.0288. There are 8 homozygotes in gnomad4. There are 388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.1054C>A	p.Pro352Thr	missense_variant	8/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.1081C>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.1054C>A	p.Pro352Thr	missense_variant	8/9	1	NM_000669.5	ENSP00000426083	P1

Frequencies

GnomAD3 genomes AF: 0.00521 AC: 790 AN: 151602 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00959 AC: 2376 AN: 247630 Hom.: 62 AF XY: 0.00775 AC XY: 1039 AN XY: 134130

Gnomad AFR exome AF: 0.000707

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00671

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00405 AC: 5885 AN: 1454452 Hom.: 81 Cov.: 31 AF XY: 0.00380 AC XY: 2750 AN XY: 723440

Gnomad4 AFR exome AF: 0.000604

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00355

Gnomad4 FIN exome AF: 0.00759

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.00525 AC: 796 AN: 151720 Hom.: 8 Cov.: 32 AF XY: 0.00524 AC XY: 388 AN XY: 74108

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00264 Hom.: 5

Bravo AF: 0.00890

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00230 AC: 10

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00799 AC: 969

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0046	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.15	T
Polyphen		0.089	B
Vest4		0.20
MVP		0.55
GERP RS		3.0
Varity_R		0.33
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs35719513; hg19: chr4-100260783;