rs148534811

Variant names:

• chr4-99207569-C-T
• rs148534811
• NM_001102470.2:c.841G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001102470.2(ADH6):​c.841G>A​(p.Ala281Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: ADH6 NM_001102470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040654153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH6	NM_001102470.2	c.841G>A	p.Ala281Thr	missense_variant	Exon 7 of 9	ENST00000394899.6	NP_001095940.1
ADH6	NM_000672.4	c.841G>A	p.Ala281Thr	missense_variant	Exon 7 of 8		NP_000663.1
ADH6	NR_132990.2	n.576G>A		non_coding_transcript_exon_variant	Exon 5 of 7
LOC100507053	NR_037884.1	n.3789+3138C>T		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH6	ENST00000394899.6	c.841G>A	p.Ala281Thr	missense_variant	Exon 7 of 9	2	NM_001102470.2	ENSP00000378359.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250536 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135384

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000926

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461050 Hom.: 1 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 726816

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000989 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841G>A (p.A281T) alteration is located in exon 7 (coding exon 7) of the ADH6 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the alanine (A) at amino acid position 281 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.9
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.021	D;D;.
Polyphen		0.96	D;B;.
Vest4		0.065
MVP		0.24
MPC		0.097
ClinPred		0.063	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs148534811; hg19: chr4-100128726;