chr4-99075043-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000671.4(ADH5):c.832G>C(p.Ala278Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,608,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
ADH5
NM_000671.4 missense
NM_000671.4 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 7.05
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.936
PP5
?
Variant 4-99075043-C-G is Pathogenic according to our data. Variant chr4-99075043-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 995827.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADH5 | NM_000671.4 | c.832G>C | p.Ala278Pro | missense_variant | 7/9 | ENST00000296412.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADH5 | ENST00000296412.14 | c.832G>C | p.Ala278Pro | missense_variant | 7/9 | 1 | NM_000671.4 | P1 | |
ADH5 | ENST00000626055.2 | c.*519G>C | 3_prime_UTR_variant | 6/8 | 5 | ||||
ADH5 | ENST00000512621.5 | n.820G>C | non_coding_transcript_exon_variant | 6/7 | 2 | ||||
ADH5 | ENST00000512659.5 | c.*519G>C | 3_prime_UTR_variant, NMD_transcript_variant | 6/6 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 245250Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133080
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1456808Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4AN XY: 724652
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
AMED syndrome, digenic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 21, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0723);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at