NM_001102470.2:c.818T>C

Variant names:

• chr4-99208678-A-G
• rs1731120946
• NM_001102470.2:c.818T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001102470.2(ADH6):​c.818T>C​(p.Leu273Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADH6 NM_001102470.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.258
• Publications: 0 publications found

Genes affected

ADH6 (HGNC:255): (alcohol dehydrogenase 6 (class V)) This gene encodes class V alcohol dehydrogenase, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This gene is expressed in the stomach as well as in the liver, and it contains a glucocorticoid response element upstream of its 5' UTR, which is a steroid hormone receptor binding site. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000246090 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055878043).
• BP6: Variant 4-99208678-A-G is Benign according to our data. Variant chr4-99208678-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3273032.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH6	NM_001102470.2	c.818T>C	p.Leu273Pro	missense_variant	Exon 6 of 9	ENST00000394899.6	NP_001095940.1
ADH6	NM_000672.4	c.818T>C	p.Leu273Pro	missense_variant	Exon 6 of 8		NP_000663.1
ADH6	NR_132990.2	n.553T>C		non_coding_transcript_exon_variant	Exon 4 of 7
LOC100507053	NR_037884.1	n.3789+4247A>G		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH6	ENST00000394899.6	c.818T>C	p.Leu273Pro	missense_variant	Exon 6 of 9	2	NM_001102470.2	ENSP00000378359.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460680 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726650

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111430

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.8
DANN	Benign	0.58
DEOGEN2	Benign	0.12	.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.33	.;N;N;.
PhyloP100		0.26
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D;N;N;D
REVEL	Benign	0.13
Sift	Benign	0.096	T;T;T;T
Sift4G	Benign	0.077	T;T;T;.
Polyphen		0.0030, 0.0020	.;B;B;.
Vest4		0.11
MutPred		0.38		Loss of stability (P = 0.0152);Loss of stability (P = 0.0152);Loss of stability (P = 0.0152);.;
MVP		0.16
MPC		0.16
ClinPred		0.043	T
GERP RS		1.4
Varity_R		0.14
gMVP		0.72
Mutation Taster		=96/4	polymorphism

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: rs1731120946; hg19: chr4-100129835;