11-107510900-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_138775.3(ALKBH8):āc.1424A>Gā(p.His475Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,551,244 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 (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000050 ( 0 hom. )
Consequence
ALKBH8
NM_138775.3 missense
NM_138775.3 missense
Scores
10
5
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 7.74
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALKBH8 | NM_138775.3 | c.1424A>G | p.His475Arg | missense_variant | 11/12 | ENST00000428149.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALKBH8 | ENST00000428149.7 | c.1424A>G | p.His475Arg | missense_variant | 11/12 | 1 | NM_138775.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000257 AC: 4AN: 155924Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82472
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GnomAD4 exome AF: 0.00000500 AC: 7AN: 1399096Hom.: 0 Cov.: 30 AF XY: 0.00000725 AC XY: 5AN XY: 690026
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74312
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0238);Gain of MoRF binding (P = 0.0238);.;
MVP
MPC
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D
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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