4-99131667-C-A

Variant names:

• chr4-99131667-C-A
• rs142365973
• NM_000670.5:c.680G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000670.5(ADH4):​c.680G>T​(p.Gly227Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,130 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.307

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023301274).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5	c.680G>T	p.Gly227Val	missense_variant	Exon 6 of 9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.737G>T	p.Gly246Val	missense_variant	Exon 7 of 10		NP_001293100.1
ADH4	NM_001306172.2	c.737G>T	p.Gly246Val	missense_variant	Exon 7 of 10		NP_001293101.1
LOC100507053	NR_037884.1	n.429-1888C>A		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.680G>T	p.Gly227Val	missense_variant	Exon 6 of 9	1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00104 AC: 261 AN: 251354 Hom.: 0 AF XY: 0.000950 AC XY: 129 AN XY: 135842

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00238 AC: 3476 AN: 1461864 Hom.: 6 Cov.: 36 AF XY: 0.00229 AC XY: 1662 AN XY: 727236

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74454

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00128

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00245

EpiControl AF: 0.00190

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680G>T (p.G227V) alteration is located in exon 6 (coding exon 6) of the ADH4 gene. This alteration results from a G to T substitution at nucleotide position 680, causing the glycine (G) at amino acid position 227 to be replaced by a valine (V). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.080	.;T;T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.84	.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.9	D;.;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.033	D;.;D;D;D
Sift4G	Benign	0.095	T;T;T;T;.
Polyphen		0.48	P;.;P;P;.
Vest4		0.34
MVP		0.18
MPC		0.048
ClinPred		0.049	T
GERP RS		-0.94
Varity_R		0.69
gMVP		0.75

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: rs142365973; hg19: chr4-100052818; COSMIC: COSV99039257; COSMIC: COSV99039257;