4-99216262-C-A

Position:

• chr4-99216262-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001102470.2(ADH6):​c.19G>T​(p.Val7Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000427 in 1,404,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ADH6 NM_001102470.2 missense, splice_region
• Scores: Splicing: ADA: 0.9904
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH6	NM_001102470.2	c.19G>T	p.Val7Phe	missense_variant, splice_region_variant	2/9	ENST00000394899.6	NP_001095940.1
ADH6	NM_000672.4	c.19G>T	p.Val7Phe	missense_variant, splice_region_variant	2/8		NP_000663.1
ADH6	NR_132990.2	n.113G>T		splice_region_variant, non_coding_transcript_exon_variant	2/7
LOC100507053	NR_037884.1	n.3789+11831C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH6	ENST00000394899.6	c.19G>T	p.Val7Phe	missense_variant, splice_region_variant	2/9	2	NM_001102470.2	ENSP00000378359.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1404684 Hom.: 0 Cov.: 30 AF XY: 0.00000430 AC XY: 3 AN XY: 698420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000553

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.19G>T (p.V7F) alteration is located in exon 2 (coding exon 2) of the ADH6 gene. This alteration results from a G to T substitution at nucleotide position 19, causing the valine (V) at amino acid position 7 to be replaced by a phenylalanine (F). 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	0.19
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	.;M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;.
Polyphen		0.97, 1.0	.;D;D;.
Vest4		0.59
MutPred		0.45		Loss of glycosylation at T3 (P = 0.0424);Loss of glycosylation at T3 (P = 0.0424);Loss of glycosylation at T3 (P = 0.0424);Loss of glycosylation at T3 (P = 0.0424);
MVP		0.55
MPC		0.44
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1474736005; hg19: chr4-100137419;