Variant 17-18184521-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017758.4(ALKBH5):c.278G>A(p.Arg93His) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ALKBH5
NM_017758.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.67

Variant links:

Genes affected

ALKBH5 (HGNC:25996): (alkB homolog 5, RNA demethylase) Enables mRNA N6-methyladenosine dioxygenase activity. Involved in RNA metabolic process; mRNA export from nucleus; and response to hypoxia. Located in Golgi apparatus; cytosol; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ALKBH5 links:

ENSG00000266677 (HGNC:):

ENSG00000266677 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1240893).

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKBH5	NM_017758.4 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	1/4	ENST00000399138.5	NP_060228.3	Q6P6C2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALKBH5	ENST00000399138.5 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	1/4	2	NM_017758.4	ENSP00000382091.4	Q6P6C2-2
ALKBH5	ENST00000541285.1 linkuse as main transcript	c.-254+1256G>A		intron_variant		1		ENSP00000468116.1	K7ER58
ENSG00000266677	ENST00000583062.1 linkuse as main transcript	n.233C>T		non_coding_transcript_exon_variant	1/2	1
ENSG00000266677	ENST00000577847.1 linkuse as main transcript	n.147C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000110

AC:

AN:

246468

Hom.:

AF XY:

0.0000966

AC XY:

AN XY:

134540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1460828

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

203

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000210

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2024

The c.278G>A (p.R93H) alteration is located in exon 1 (coding exon 1) of the ALKBH5 gene. This alteration results from a G to A substitution at nucleotide position 278, causing the arginine (R) at amino acid position 93 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0095

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.0

REVEL

Benign

0.088

Sift

Benign

0.096

Sift4G

Benign

0.11

Vest4

0.38

MVP

0.38

MPC

2.6

ClinPred

0.26

GERP RS

3.8

Varity_R

0.45

gMVP

0.53

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