4-99208910-A-C

Variant names:

• chr4-99208910-A-C
• rs1731130840
• NM_001102470.2:c.586T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001102470.2(ADH6):​c.586T>G​(p.Cys196Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C196R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH6 NM_001102470.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.46
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102470.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH6	NM_001102470.2	MANE Select	c.586T>G	p.Cys196Gly	missense	Exon 6 of 9	NP_001095940.1	P28332-2
	ADH6	NM_000672.4		c.586T>G	p.Cys196Gly	missense	Exon 6 of 8	NP_000663.1	P28332-1
	ADH6	NR_132990.2		n.321T>G		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH6	ENST00000394899.6	TSL:2 MANE Select	c.586T>G	p.Cys196Gly	missense	Exon 6 of 9	ENSP00000378359.2	P28332-2
	ENSG00000246090	ENST00000500358.6	TSL:1	n.3789+4479A>C		intron	N/A
	ADH6	ENST00000881183.1		c.607T>G	p.Cys203Gly	missense	Exon 6 of 9	ENSP00000551242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		6.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-12	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.80		Gain of disorder (P = 0.0173)
MVP		0.60
MPC		0.56
ClinPred		1.0	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.37
gMVP		0.87
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1731130840; hg19: chr4-100130067;