Genetic Variant NM_000670.5:c.925A>C (chr4-99127263-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000670.5(ADH4):c.925A>C(p.Ile309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I309F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADH4
NM_000670.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.88

Publications

75 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07115093).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADH4	NM_000670.5	MANE Select	c.925A>C	p.Ile309Leu	missense	Exon 7 of 9	NP_000661.2	P08319-1
ADH4	NM_001306171.2		c.982A>C	p.Ile328Leu	missense	Exon 8 of 10	NP_001293100.1	P08319-2
ADH4	NM_001306172.2		c.982A>C	p.Ile328Leu	missense	Exon 8 of 10	NP_001293101.1	P08319-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADH4	ENST00000265512.12	TSL:1 MANE Select	c.925A>C	p.Ile309Leu	missense	Exon 7 of 9	ENSP00000265512.7	P08319-1
ENSG00000246090	ENST00000500358.6	TSL:1	n.429-6292T>G		intron	N/A
ADH4	ENST00000505590.5	TSL:5	c.982A>C	p.Ile328Leu	missense	Exon 8 of 10	ENSP00000425416.1	P08319-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1459518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726142

African (AFR)

AF:

0.00

AC:

AN:

33338

American (AMR)

AF:

0.00

AC:

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

85988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110600

Other (OTH)

AF:

0.00

AC:

AN:

60254

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.052

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.0087

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.17

M_CAP

Benign

0.0021

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.20

PhyloP100

-1.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.46

REVEL

Benign

0.014

Sift

Benign

0.56

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.11

MutPred

0.38

Loss of catalytic residue at P311 (P = 0.0712)

MVP

0.18

MPC

0.038

ClinPred

0.033

GERP RS

-7.3

Varity_R

0.064

gMVP

0.52

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over