Genetic Variant ADH4:p.Leu351Leu (chr4-99126661-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000670.5(ADH4):c.1051C>T(p.Leu351Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,610,126 control chromosomes in the GnomAD database, including 53,540 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 0.21 ( 4047 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49493 hom. )

Consequence

ADH4
NM_000670.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0210

Publications

40 publications found

Variant links:

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]

ADH4 links:

ENSG00000246090 (HGNC:):

ENSG00000246090 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP7

Synonymous conserved (PhyloP=0.021 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5 link	c.1051C>T	p.Leu351Leu	synonymous_variant	Exon 8 of 9	ENST00000265512.12	NP_000661.2	P08319-1V9HVX7
ADH4	NM_001306171.2 link	c.1108C>T	p.Leu370Leu	synonymous_variant	Exon 9 of 10		NP_001293100.1	P08319-2V9HVX7
ADH4	NM_001306172.2 link	c.1108C>T	p.Leu370Leu	synonymous_variant	Exon 9 of 10		NP_001293101.1	P08319-2V9HVX7
LOC100507053	NR_037884.1 link	n.429-6894G>A		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12 link	c.1051C>T	p.Leu351Leu	synonymous_variant	Exon 8 of 9	1	NM_000670.5	ENSP00000265512.7		P08319-1

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

32040

AN:

152042

Hom.:

4050

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.240

GnomAD2 exomes

AF:

0.208

AC:

52179

AN:

251012

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.251

AC:

365928

AN:

1457966

Hom.:

49493

Cov.:

AF XY:

0.249

AC XY:

180803

AN XY:

725252

show subpopulations

African (AFR)

AF:

0.102

AC:

3417

AN:

33460

American (AMR)

AF:

0.143

AC:

6388

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7858

AN:

25966

East Asian (EAS)

AF:

0.00154

AC:

AN:

39680

South Asian (SAS)

AF:

0.129

AC:

11031

AN:

85792

European-Finnish (FIN)

AF:

0.240

AC:

12781

AN:

53196

Middle Eastern (MID)

AF:

0.243

AC:

1400

AN:

5750

European-Non Finnish (NFE)

AF:

0.278

AC:

308534

AN:

1109294

Other (OTH)

AF:

0.240

AC:

14458

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

13279

26557

39836

53114

66393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9924

19848

29772

39696

49620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.211

AC:

32041

AN:

152160

Hom.:

4047

Cov.:

AF XY:

0.203

AC XY:

15096

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.109

AC:

4534

AN:

41524

American (AMR)

AF:

0.208

AC:

3182

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1037

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.116

AC:

559

AN:

4824

European-Finnish (FIN)

AF:

0.233

AC:

2468

AN:

10574

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19373

AN:

67974

Other (OTH)

AF:

0.238

AC:

503

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1253

2506

3758

5011

6264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.255

Hom.:

18810

Bravo

AF:

0.204

Asia WGS

AF:

0.0680

AC:

238

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.44

(source)

DANN

Benign

0.60

PhyloP100

0.021

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over