chr4-99124423-T-C

Position:

• chr4-99124423-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000670.5(ADH4):​c.*19A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,459,260 control chromosomes in the GnomAD database, including 408,810 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.79 (48068 hom., cov: 32)
  • Exomes 𝑓: 0.74 (360742 hom.)
• Consequence: ADH4 NM_000670.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.500

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.252315E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.*19A>G		3_prime_UTR_variant	9/9	ENST00000265512.12	NP_000661.2
LOC100507053	NR_037884.1	n.429-9132T>C		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.*19A>G		3_prime_UTR_variant	10/10		NP_001293100.1
ADH4	NM_001306172.2	c.*19A>G		3_prime_UTR_variant	10/10		NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.*19A>G		3_prime_UTR_variant	9/9	1	NM_000670.5	ENSP00000265512	P1
	ENST00000500358.6	n.429-9132T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119970 AN: 152018 Hom.: 48014 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.760

GnomAD3 exomes AF: 0.785 AC: 182653 AN: 232700 Hom.: 72918 AF XY: 0.779 AC XY: 97839 AN XY: 125612

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.698

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.764

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.736 AC: 962632 AN: 1307124 Hom.: 360742 Cov.: 23 AF XY: 0.739 AC XY: 484269 AN XY: 655170

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.864

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.706

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.789 AC: 120085 AN: 152136 Hom.: 48068 Cov.: 32 AF XY: 0.797 AC XY: 59253 AN XY: 74358

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.792

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.883

Gnomad4 FIN AF: 0.767

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.763

Alfa AF: 0.727 Hom.: 60202

Bravo AF: 0.796

TwinsUK AF: 0.716 AC: 2654

ALSPAC AF: 0.723 AC: 2786

ESP6500AA AF: 0.890 AC: 3916

ESP6500EA AF: 0.711 AC: 6113

ExAC AF: 0.784 AC: 95124

Asia WGS AF: 0.932 AC: 3237 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.69
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	9.3e-7	T
MutationTaster	Benign	0.038	P;P;P;P
Vest4		0.11
GERP RS		2.3

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: rs1042364; hg19: chr4-100045574;