Variant 11-107504696-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_138775.3(ALKBH8):c.1957G>T(p.Asp653Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,549,788 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.018 ( 287 hom. )

Consequence

ALKBH8
NM_138775.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.63

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 Benign. Variant got -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.009800017).

BP6

Variant 11-107504696-C-A is Benign according to our data. Variant chr11-107504696-C-A is described in ClinVar as [Benign]. Clinvar id is 3038293.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0132 (2011/152100) while in subpopulation SAS AF= 0.0337 (162/4810). AF 95% confidence interval is 0.0294. There are 24 homozygotes in gnomad4. There are 948 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALKBH8	NM_138775.3 link	c.1957G>T	p.Asp653Tyr	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.1957G>T	p.Asp653Tyr	missense_variant	Exon 12 of 12	1	NM_138775.3	ENSP00000415885.2		Q96BT7-1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2009

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.0102

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0176

AC:

2747

AN:

156430

Hom.:

AF XY:

0.0196

AC XY:

1613

AN XY:

82406

show subpopulations

Gnomad AFR exome

AF:

0.00408

Gnomad AMR exome

AF:

0.00668

Gnomad ASJ exome

AF:

0.0464

Gnomad EAS exome

AF:

0.000184

Gnomad SAS exome

AF:

0.0288

Gnomad FIN exome

AF:

0.00986

Gnomad NFE exome

AF:

0.0211

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0179

AC:

25080

AN:

1397688

Hom.:

287

Cov.:

AF XY:

0.0186

AC XY:

12808

AN XY:

689278

show subpopulations

Gnomad4 AFR exome

AF:

0.00270

Gnomad4 AMR exome

AF:

0.00716

Gnomad4 ASJ exome

AF:

0.0467

Gnomad4 EAS exome

AF:

0.000140

Gnomad4 SAS exome

AF:

0.0302

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.0181

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0132

AC:

2011

AN:

152100

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

948

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00287

Gnomad4 AMR

AF:

0.00596

Gnomad4 ASJ

AF:

0.0438

Gnomad4 EAS

AF:

0.000968

Gnomad4 SAS

AF:

0.0337

Gnomad4 FIN

AF:

0.0102

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0186

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.00578

AC:

ESP6500EA

AF:

0.0211

AC:

ExAC

AF:

0.0225

AC:

581

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ALKBH8-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D

MetaRNN

Benign

0.0098

T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.5

M;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.6

D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.51

MPC

0.063

ClinPred

0.11

GERP RS

5.1

Varity_R

0.92

gMVP

0.62

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