4-99127355-G-A

Variant names:

• chr4-99127355-G-A
• rs6836440
• NM_000670.5:c.844-11C>T

Variant summary

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

The NM_000670.5(ADH4):​c.844-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,582,896 control chromosomes in the GnomAD database, including 744,486 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 0.96 (70031 hom., cov: 32)
  • Exomes 𝑓: 0.97 (674455 hom.)
• Consequence: ADH4 NM_000670.5 intron
• Scores: Splicing: ADA: 0.00002529
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.726
• Publications: 10 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 (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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.844-11C>T		intron	N/A	NP_000661.2	P08319-1
	ADH4	NM_001306171.2		c.901-11C>T		intron	N/A	NP_001293100.1	P08319-2
	ADH4	NM_001306172.2		c.901-11C>T		intron	N/A	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.844-11C>T		intron	N/A	ENSP00000265512.7	P08319-1
	ENSG00000246090	ENST00000500358.6	TSL:1	n.429-6200G>A		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.901-11C>T		intron	N/A	ENSP00000425416.1	P08319-2

Frequencies

GnomAD3 genomes AF: 0.959 AC: 145906 AN: 152154 Hom.: 69981 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.973

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.979

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.964 AC: 222815 AN: 231060 AF XY: 0.968

Gnomad AFR exome AF: 0.929

Gnomad AMR exome AF: 0.931

Gnomad ASJ exome AF: 0.979

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.941

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.966

GnomAD4 exome AF: 0.971 AC: 1388970 AN: 1430624 Hom.: 674455 Cov.: 32 AF XY: 0.971 AC XY: 691076 AN XY: 711358

African (AFR) AF: 0.930 AC: 29851 AN: 32084

American (AMR) AF: 0.932 AC: 37030 AN: 39718

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 24571 AN: 25120

East Asian (EAS) AF: 1.00 AC: 38746 AN: 38752

South Asian (SAS) AF: 0.982 AC: 78327 AN: 79794

European-Finnish (FIN) AF: 0.941 AC: 49626 AN: 52722

Middle Eastern (MID) AF: 0.986 AC: 5559 AN: 5638

European-Non Finnish (NFE) AF: 0.973 AC: 1067913 AN: 1097816

Other (OTH) AF: 0.972 AC: 57347 AN: 58980

GnomAD4 genome AF: 0.959 AC: 146015 AN: 152272 Hom.: 70031 Cov.: 32 AF XY: 0.959 AC XY: 71404 AN XY: 74436

African (AFR) AF: 0.934 AC: 38781 AN: 41536

American (AMR) AF: 0.956 AC: 14634 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.973 AC: 3376 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5174

South Asian (SAS) AF: 0.979 AC: 4727 AN: 4828

European-Finnish (FIN) AF: 0.944 AC: 10019 AN: 10610

Middle Eastern (MID) AF: 0.983 AC: 287 AN: 292

European-Non Finnish (NFE) AF: 0.971 AC: 66078 AN: 68034

Other (OTH) AF: 0.968 AC: 2047 AN: 2114

Alfa AF: 0.964 Hom.: 23873

Bravo AF: 0.957

Asia WGS AF: 0.977 AC: 3399 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.3
DANN	Benign	0.44
PhyloP100		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs6836440; hg19: chr4-100048506;