Variant 11-107504761-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_138775.3(ALKBH8):c.1892G>A(p.Arg631His) variant causes a missense change. The variant allele was found at a frequency of 0.000245 in 1,552,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ALKBH8
NM_138775.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 3.66

Variant links:

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]

ALKBH8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0070365965).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (118/152258) while in subpopulation AFR AF= 0.00234 (97/41540). AF 95% confidence interval is 0.00196. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALKBH8	NM_138775.3 link	c.1892G>A	p.Arg631His	missense_variant	Exon 12 of 12	ENST00000428149.7	NP_620130.2	Q96BT7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALKBH8	ENST00000428149.7 link	c.1892G>A	p.Arg631His	missense_variant	Exon 12 of 12	1	NM_138775.3	ENSP00000415885.2		Q96BT7-1

Frequencies

GnomAD3 genomes

AF:

0.000776

AC:

118

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000322

AC:

AN:

158230

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

83368

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000917

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.0000589

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000188

AC:

263

AN:

1399830

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

109

AN XY:

690384

show subpopulations

Gnomad4 AFR exome

AF:

0.00225

Gnomad4 AMR exome

AF:

0.000308

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.000292

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152258

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00234

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.000933

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual developmental disorder, autosomal recessive 71

Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALKBH8-related disorder

Benign:1

Mar 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

-0.0078

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.0080

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

L;L;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.077

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.81

P;P;B

Vest4

0.069

MVP

0.44

MPC

0.0099

ClinPred

0.023

GERP RS

5.3

Varity_R

0.078

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over