NM_000670.5:c.893T>C

Variant names:

• chr4-99127295-A-G
• rs367861880
• NM_000670.5:c.893T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000670.5(ADH4):​c.893T>C​(p.Ile298Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,612,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

Genes affected

ADH4 (HGNC:252): (alcohol dehydrogenase 4 (class II), pi polypeptide) This gene encodes class II alcohol dehydrogenase 4 pi subunit, which is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class II alcohol dehydrogenase is a homodimer composed of 2 pi subunits. It exhibits a high activity for oxidation of long-chain aliphatic alcohols and aromatic alcohols and is less sensitive to pyrazole. This gene is localized to chromosome 4 in the cluster of alcohol dehydrogenase genes. [provided by RefSeq, Jul 2008]

ENSG00000246090 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093250126).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000670.5. 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
	ADH4	NM_000670.5	MANE Select	c.893T>C	p.Ile298Thr	missense	Exon 7 of 9	NP_000661.2	P08319-1
	ADH4	NM_001306171.2		c.950T>C	p.Ile317Thr	missense	Exon 8 of 10	NP_001293100.1	P08319-2
	ADH4	NM_001306172.2		c.950T>C	p.Ile317Thr	missense	Exon 8 of 10	NP_001293101.1	P08319-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH4	ENST00000265512.12	TSL:1 MANE Select	c.893T>C	p.Ile298Thr	missense	Exon 7 of 9	ENSP00000265512.7	P08319-1
	ENSG00000246090	ENST00000500358.6	TSL:1	n.429-6260A>G		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.950T>C	p.Ile317Thr	missense	Exon 8 of 10	ENSP00000425416.1	P08319-2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000184 AC: 46 AN: 250312 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.0000719 AC: 105 AN: 1460254 Hom.: 0 Cov.: 35 AF XY: 0.0000633 AC XY: 46 AN XY: 726482

African (AFR) AF: 0.0000599 AC: 2 AN: 33386

American (AMR) AF: 0.000493 AC: 22 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111024

Other (OTH) AF: 0.000298 AC: 18 AN: 60306

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.000720 AC: 11 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Benign	0.074
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.45
MVP		0.44
MPC		0.067
ClinPred		0.11	T
GERP RS		3.6
Varity_R		0.55
gMVP		0.73
Mutation Taster		=84/16	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: rs367861880; hg19: chr4-100048446;