rs1126673

Variant names:

• chr4-99124465-C-T
• rs1126673
• NM_000670.5:c.1120G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000670.5(ADH4):​c.1120G>A​(p.Val374Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,439,334 control chromosomes in the GnomAD database, including 368,453 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (43168 hom., cov: 33)
  • Exomes 𝑓: 0.70 (325285 hom.)
• Consequence: ADH4 NM_000670.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003198
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499
• Publications: 46 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3326764E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5	c.1120G>A	p.Val374Ile	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.1177G>A	p.Val393Ile	missense_variant, splice_region_variant	Exon 10 of 10		NP_001293100.1
ADH4	NM_001306172.2	c.1177G>A	p.Val393Ile	missense_variant, splice_region_variant	Exon 10 of 10		NP_001293101.1
LOC100507053	NR_037884.1	n.429-9090C>T		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.1120G>A	p.Val374Ile	missense_variant, splice_region_variant	Exon 9 of 9	1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113770 AN: 152050 Hom.: 43122 Cov.: 33

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.746 AC: 169887 AN: 227800 AF XY: 0.743

Gnomad AFR exome AF: 0.819

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.676

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.704

Gnomad NFE exome AF: 0.678

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.703 AC: 905488 AN: 1287166 Hom.: 325285 Cov.: 22 AF XY: 0.707 AC XY: 456382 AN XY: 645440

African (AFR) AF: 0.818 AC: 23595 AN: 28860

American (AMR) AF: 0.780 AC: 31352 AN: 40192

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 16532 AN: 24772

East Asian (EAS) AF: 0.998 AC: 37154 AN: 37216

South Asian (SAS) AF: 0.844 AC: 63724 AN: 75524

European-Finnish (FIN) AF: 0.699 AC: 36823 AN: 52694

Middle Eastern (MID) AF: 0.732 AC: 3875 AN: 5294

European-Non Finnish (NFE) AF: 0.675 AC: 653543 AN: 968370

Other (OTH) AF: 0.717 AC: 38890 AN: 54244

GnomAD4 genome AF: 0.748 AC: 113876 AN: 152168 Hom.: 43168 Cov.: 33 AF XY: 0.756 AC XY: 56244 AN XY: 74364

African (AFR) AF: 0.825 AC: 34237 AN: 41524

American (AMR) AF: 0.748 AC: 11441 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2340 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5169 AN: 5180

South Asian (SAS) AF: 0.863 AC: 4160 AN: 4820

European-Finnish (FIN) AF: 0.711 AC: 7508 AN: 10560

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.686 AC: 46673 AN: 68004

Other (OTH) AF: 0.731 AC: 1543 AN: 2110

Alfa AF: 0.707 Hom.: 121460

Bravo AF: 0.753

TwinsUK AF: 0.686 AC: 2544

ALSPAC AF: 0.697 AC: 2686

ESP6500AA AF: 0.823 AC: 3623

ESP6500EA AF: 0.683 AC: 5868

ExAC AF: 0.749 AC: 90822

Asia WGS AF: 0.909 AC: 3160 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.1
DANN	Benign	0.79
DEOGEN2	Benign	0.0058	.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.35	.;T;T;T
MetaRNN	Benign	0.0000013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	.;.;N;.
PhyloP100		0.50
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.80	N;.;N;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0040	B;.;B;B
Vest4		0.038
MPC		0.033
ClinPred		0.0013	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.29
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.018
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: rs1126673; hg19: chr4-100045616; COSMIC: COSV107209574; COSMIC: COSV107209574;