NM_001102470.2:c.1033C>T

Variant names:

• chr4-99204995-G-A
• rs1401788182
• NM_001102470.2:c.1033C>T

Variant summary

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

The NM_001102470.2(ADH6):​c.1033C>T​(p.Pro345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: ADH6 NM_001102470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.200

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=0.20946422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH6	NM_001102470.2	c.1033C>T	p.Pro345Ser	missense_variant	Exon 8 of 9	ENST00000394899.6	NP_001095940.1
ADH6	NM_000672.4	c.1033C>T	p.Pro345Ser	missense_variant	Exon 8 of 8		NP_000663.1
ADH6	NR_132990.2	n.768C>T		non_coding_transcript_exon_variant	Exon 6 of 7
LOC100507053	NR_037884.1	n.3789+564G>A		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH6	ENST00000394899.6	c.1033C>T	p.Pro345Ser	missense_variant	Exon 8 of 9	2	NM_001102470.2	ENSP00000378359.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457328 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1033C>T (p.P345S) alteration is located in exon 8 (coding exon 8) of the ADH6 gene. This alteration results from a C to T substitution at nucleotide position 1033, causing the proline (P) at amino acid position 345 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.20
DANN	Benign	0.45
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.40	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.0070
Sift	Benign	0.39	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.50	P;B
Vest4		0.11
MutPred		0.26		Loss of methylation at K340 (P = 0.1511);Loss of methylation at K340 (P = 0.1511);
MVP		0.22
MPC		0.24
ClinPred		0.078	T
GERP RS		-0.43
Varity_R		0.018
gMVP		0.56

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

Other links and lift over

dbSNP: rs1401788182; hg19: chr4-100126152;