chr4-99141543-G-C

Variant names:

• chr4-99141543-G-C
• rs376943095
• NM_000670.5:c.260C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000670.5(ADH4):​c.260C>G​(p.Pro87Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000231 in 1,604,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ADH4 NM_000670.5 missense, splice_region
• Scores: Splicing: ADA: 0.001696
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.76
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.260C>G	p.Pro87Arg	missense splice_region	Exon 3 of 9	NP_000661.2	P08319-1
	ADH4	NM_001306171.2		c.317C>G	p.Pro106Arg	missense splice_region	Exon 4 of 10	NP_001293100.1	P08319-2
	ADH4	NM_001306172.2		c.317C>G	p.Pro106Arg	missense splice_region	Exon 4 of 10	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.260C>G	p.Pro87Arg	missense splice_region	Exon 3 of 9	ENSP00000265512.7	P08319-1
	ENSG00000246090	ENST00000500358.6	TSL:1	n.679+7738G>C		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.317C>G	p.Pro106Arg	missense splice_region	Exon 4 of 10	ENSP00000425416.1	P08319-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243364 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1452424 Hom.: 0 Cov.: 31 AF XY: 0.0000249 AC XY: 18 AN XY: 722362

African (AFR) AF: 0.00 AC: 0 AN: 32992

American (AMR) AF: 0.00 AC: 0 AN: 42046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 84758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000307 AC: 34 AN: 1108464

Other (OTH) AF: 0.0000167 AC: 1 AN: 59950

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.74
MVP		0.65
MPC		0.28
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.78
gMVP		0.52
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.11		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: rs376943095; hg19: chr4-100062694;