rs1126673

Positions:

• chr4-99124465-C-T

Variant summary

Our verdict is Benign. Variant got -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. 16/22 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.1120G>A	p.Val374Ile	missense_variant, splice_region_variant	9/9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.1177G>A	p.Val393Ile	missense_variant, splice_region_variant	10/10		NP_001293100.1
ADH4	NM_001306172.2	c.1177G>A	p.Val393Ile	missense_variant, splice_region_variant	10/10		NP_001293101.1
LOC100507053	NR_037884.1	n.429-9090C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.1120G>A	p.Val374Ile	missense_variant, splice_region_variant	9/9	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

GnomAD3 exomes AF: 0.746 AC: 169887 AN: 227800 Hom.: 64553 AF XY: 0.743 AC XY: 91443 AN XY: 123016

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 SAS exome AF: 0.842

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

Gnomad4 AFR exome AF: 0.818

Gnomad4 AMR exome AF: 0.780

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.844

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.717

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

Gnomad4 AFR AF: 0.825

Gnomad4 AMR AF: 0.748

Gnomad4 ASJ AF: 0.674

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.863

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.686

Gnomad4 OTH AF: 0.731

Alfa AF: 0.703 Hom.: 93508

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;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1126673; hg19: chr4-100045616;