Genetic Variant NM_000671.4:c.13-278T>C (chr4-99085494-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000671.4(ADH5):c.13-278T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 303,480 control chromosomes in the GnomAD database, including 92,642 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 ( 47728 hom., cov: 33)

Exomes 𝑓: 0.77 ( 44914 hom. )

Consequence

ADH5
NM_000671.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.233

Publications

8 publications found

Variant links:

Genes affected

ADH5 (HGNC:253): (alcohol dehydrogenase 5 (class III), chi polypeptide) This gene encodes a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The encoded protein forms a homodimer. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. The human genome contains several non-transcribed pseudogenes related to this gene. [provided by RefSeq, Oct 2008]

ADH5 Gene-Disease associations (from GenCC):

AMED syndrome, digenic
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ADH5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH5	NM_000671.4 link	c.13-278T>C		intron_variant	Intron 1 of 8	ENST00000296412.14	NP_000662.3	P11766Q6IRT1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH5	ENST00000296412.14 link	c.13-278T>C		intron_variant	Intron 1 of 8	1	NM_000671.4	ENSP00000296412.8		P11766

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119691

AN:

152128

Hom.:

47676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.877

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.798

Gnomad ASJ

AF:

0.698

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.884

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.718

Gnomad OTH

AF:

0.757

GnomAD4 exome

AF:

0.766

AC:

115859

AN:

151234

Hom.:

44914

Cov.:

AF XY:

0.768

AC XY:

59917

AN XY:

78050

show subpopulations

African (AFR)

AF:

0.881

AC:

4452

AN:

5056

American (AMR)

AF:

0.841

AC:

4352

AN:

5174

Ashkenazi Jewish (ASJ)

AF:

0.698

AC:

3954

AN:

5664

East Asian (EAS)

AF:

0.998

AC:

11283

AN:

11302

South Asian (SAS)

AF:

0.876

AC:

7379

AN:

8424

European-Finnish (FIN)

AF:

0.759

AC:

7564

AN:

9966

Middle Eastern (MID)

AF:

0.740

AC:

1778

AN:

2404

European-Non Finnish (NFE)

AF:

0.723

AC:

67431

AN:

93228

Other (OTH)

AF:

0.765

AC:

7666

AN:

10016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1284

2568

3851

5135

6419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.787

AC:

119804

AN:

152246

Hom.:

47728

Cov.:

AF XY:

0.794

AC XY:

59130

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.877

AC:

36468

AN:

41566

American (AMR)

AF:

0.798

AC:

12202

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.698

AC:

2423

AN:

3472

East Asian (EAS)

AF:

0.997

AC:

5171

AN:

5186

South Asian (SAS)

AF:

0.884

AC:

4269

AN:

4830

European-Finnish (FIN)

AF:

0.759

AC:

8035

AN:

10590

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.718

AC:

48793

AN:

67998

Other (OTH)

AF:

0.760

AC:

1603

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1279

2558

3836

5115

6394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.755

Hom.:

78838

Bravo

AF:

0.794

Asia WGS

AF:

0.931

AC:

3235

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

-0.23

PromoterAI

0.0060

Neutral

(source)

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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NM_000671.4:c.13-278T>C

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