rs35719513

Variant names:

• chr4-99339626-G-T
• rs35719513
• NM_000669.5:c.1054C>A

Variant summary

Our verdict is Benign. The variant received -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 (★★).

• 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
• Publications: 14 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000669.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	NM_000669.5	MANE Select	c.1054C>A	p.Pro352Thr	missense	Exon 8 of 9	NP_000660.1	P00326
	ADH1C	NR_133005.2		n.1081C>A		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.1054C>A	p.Pro352Thr	missense	Exon 8 of 9	ENSP00000426083.1	P00326
	ADH1C	ENST00000865215.1		c.1054C>A	p.Pro352Thr	missense	Exon 9 of 10	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.1054C>A	p.Pro352Thr	missense	Exon 9 of 10	ENSP00000535275.1

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

GnomAD2 exomes AF: 0.00959 AC: 2376 AN: 247630 AF XY: 0.00775

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 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

African (AFR) AF: 0.000604 AC: 20 AN: 33094

American (AMR) AF: 0.0517 AC: 2268 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39532

South Asian (SAS) AF: 0.00355 AC: 302 AN: 85188

European-Finnish (FIN) AF: 0.00759 AC: 401 AN: 52820

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5718

European-Non Finnish (NFE) AF: 0.00238 AC: 2643 AN: 1108284

Other (OTH) AF: 0.00406 AC: 244 AN: 60036

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

African (AFR) AF: 0.000701 AC: 29 AN: 41346

American (AMR) AF: 0.0311 AC: 472 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4814

European-Finnish (FIN) AF: 0.00602 AC: 63 AN: 10464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 67964

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00337 Hom.: 12

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.9
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

Other links and lift over

dbSNP: rs35719513; hg19: chr4-100260783;