4-99205011-C-A

Position:

• chr4-99205011-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102470.2(ADH6):​c.1017G>T​(p.Glu339Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ADH6 NM_001102470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.193

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12695608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH6	NM_001102470.2	c.1017G>T	p.Glu339Asp	missense_variant	8/9	ENST00000394899.6	NP_001095940.1
ADH6	NM_000672.4	c.1017G>T	p.Glu339Asp	missense_variant	8/8		NP_000663.1
ADH6	NR_132990.2	n.752G>T		non_coding_transcript_exon_variant	6/7
LOC100507053	NR_037884.1	n.3789+580C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH6	ENST00000394899.6	c.1017G>T	p.Glu339Asp	missense_variant	8/9	2	NM_001102470.2	ENSP00000378359.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456366 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5 AN XY: 724514

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 04, 2024

The c.1017G>T (p.E339D) alteration is located in exon 8 (coding exon 8) of the ADH6 gene. This alteration results from a G to T substitution at nucleotide position 1017, causing the glutamic acid (E) at amino acid position 339 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.060	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.046
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.49		Gain of glycosylation at Y336 (P = 0.0217);Gain of glycosylation at Y336 (P = 0.0217);
MVP		0.41
MPC		0.087
ClinPred		0.12	T
GERP RS		2.0
Varity_R		0.055
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100126168; COSMIC: COSV52955169; COSMIC: COSV52955169;