4-99072706-TC-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000671.4(ADH5):c.966delG(p.Trp322fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,605,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000671.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADH5 | ENST00000296412.14 | c.966delG | p.Trp322fs | frameshift_variant | Exon 8 of 9 | 1 | NM_000671.4 | ENSP00000296412.8 | ||
ADH5 | ENST00000626055 | c.*653delG | 3_prime_UTR_variant | Exon 7 of 8 | 5 | ENSP00000487496.1 | ||||
ADH5 | ENST00000512621.5 | n.954delG | non_coding_transcript_exon_variant | Exon 7 of 7 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000373 AC: 9AN: 241044Hom.: 0 AF XY: 0.0000230 AC XY: 3AN XY: 130612
GnomAD4 exome AF: 0.0000227 AC: 33AN: 1453760Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12AN XY: 722758
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
AMED syndrome, digenic Pathogenic:2
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00004). The variant was observed in trans with a pathogenic variant as compound heterozygous or homozygous at multiple unrelated families (3billion dataset, PMID: 33355142, PM3_S). Patient's phenotype is considered compatible with AMED syndrome, digenic (3billion dataset, PP4).In addition, the patient carries ALDH2 heterozygous defective allele (NM_000690.4):c.1510G>A), which is considered to be associated with the severity of AMED syndrome clinical features. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at