chr11-107504693-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_138775.3(ALKBH8):c.1960C>T(p.Gln654Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,549,550 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000043 ( 0 hom. )
Consequence
ALKBH8
NM_138775.3 stop_gained
NM_138775.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
ALKBH8 (HGNC:25189): (alkB homolog 8, tRNA methyltransferase) Enables tRNA (uracil) methyltransferase activity; tRNA binding activity; and zinc ion binding activity. Involved in cellular response to DNA damage stimulus; tRNA methylation; and tRNA wobble uridine modification. Located in cytosol and nuclear body. Implicated in autosomal recessive non-syndromic intellectual disability. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0175 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALKBH8 | NM_138775.3 | c.1960C>T | p.Gln654Ter | stop_gained | 12/12 | ENST00000428149.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALKBH8 | ENST00000428149.7 | c.1960C>T | p.Gln654Ter | stop_gained | 12/12 | 1 | NM_138775.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151952Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000429 AC: 6AN: 1397598Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2AN XY: 689232
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74200
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2021 | Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation as the last 11 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) - |
Computational scores
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Name
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
Vest4
GERP RS
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