11-107505101-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_138775.3(ALKBH8):c.1552C>T(p.Leu518Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,551,358 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 3 hom. )

Consequence

ALKBH8
NM_138775.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.68

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021187931).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000716 (109/152162) while in subpopulation AFR AF= 0.00241 (100/41512). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 48 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

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALKBH8	NM_138775.3 link	c.1552C>T	p.Leu518Phe	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.1552C>T	p.Leu518Phe	missense_variant	Exon 12 of 12	1	NM_138775.3	ENSP00000415885.2		Q96BT7-1

Frequencies

GnomAD3 genomes

AF:

0.000704

AC:

107

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000199

AC:

AN:

156132

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

82738

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.000162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000908

AC:

127

AN:

1399196

Hom.:

Cov.:

AF XY:

0.0000768

AC XY:

AN XY:

690112

show subpopulations

Gnomad4 AFR exome

AF:

0.00307

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000883

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.000172

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152162

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000382

Hom.:

Bravo

AF:

0.000688

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000358

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1552C>T (p.L518F) alteration is located in exon 12 (coding exon 11) of the ALKBH8 gene. This alteration results from a C to T substitution at nucleotide position 1552, causing the leucine (L) at amino acid position 518 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ALKBH8-related disorder

Benign:1

Apr 18, 2022

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

Uncertain

0.38

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;D;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Pathogenic

3.5

M;M;.

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.53

MVP

0.49

MPC

0.063

ClinPred

0.15

GERP RS

5.2

Varity_R

0.51

gMVP

0.50

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