4-99208780-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001102470.2(ADH6):​c.716C>T​(p.Thr239Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADH6
NM_001102470.2 missense

Scores

9
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.80
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADH6NM_001102470.2 linkc.716C>T p.Thr239Ile missense_variant Exon 6 of 9 ENST00000394899.6 NP_001095940.1 P28332-2Q8IUN7
ADH6NM_000672.4 linkc.716C>T p.Thr239Ile missense_variant Exon 6 of 8 NP_000663.1 P28332-1Q8IUN7
ADH6NR_132990.2 linkn.451C>T non_coding_transcript_exon_variant Exon 4 of 7
LOC100507053NR_037884.1 linkn.3789+4349G>A intron_variant Intron 4 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADH6ENST00000394899.6 linkc.716C>T p.Thr239Ile missense_variant Exon 6 of 9 2 NM_001102470.2 ENSP00000378359.2 P28332-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251358
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461646
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727140
show subpopulations
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.716C>T (p.T239I) alteration is located in exon 6 (coding exon 6) of the ADH6 gene. This alteration results from a C to T substitution at nucleotide position 716, causing the threonine (T) at amino acid position 239 to be replaced by an isoleucine (I). 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
Pathogenic
0.66
BayesDel_addAF
Benign
-0.086
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;.;T;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Pathogenic
4.2
.;H;H;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-5.9
D;D;D;D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
.;D;D;.
Vest4
0.69
MutPred
0.71
Gain of catalytic residue at T239 (P = 0.0327);Gain of catalytic residue at T239 (P = 0.0327);Gain of catalytic residue at T239 (P = 0.0327);.;
MVP
0.65
MPC
0.52
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.39
gMVP
0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771271459; hg19: chr4-100129937; API