Genetic Variant ALKBH5:p.Ala37Val (chr17-18184353-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017758.4(ALKBH5):c.110C>T(p.Ala37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,366,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ALKBH5
NM_017758.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20548564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017758.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH5	NM_017758.4	MANE Select	c.110C>T	p.Ala37Val	missense	Exon 1 of 4	NP_060228.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALKBH5	ENST00000399138.5	TSL:2 MANE Select	c.110C>T	p.Ala37Val	missense	Exon 1 of 4	ENSP00000382091.4	Q6P6C2-2
ALKBH5	ENST00000541285.1	TSL:1	c.-254+1088C>T		intron	N/A	ENSP00000468116.1	K7ER58
ENSG00000266677	ENST00000583062.2	TSL:1	n.395+44G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1366030

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673988

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28572

American (AMR)

AF:

0.0000345

AC:

AN:

29010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23964

East Asian (EAS)

AF:

0.00

AC:

AN:

33710

South Asian (SAS)

AF:

0.00

AC:

AN:

75718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4350

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1067898

Other (OTH)

AF:

0.00

AC:

AN:

56380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.032

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.19

REVEL

Benign

0.12

Sift

Benign

0.14

Sift4G

Benign

0.99

Vest4

0.23

MutPred

0.33

Gain of catalytic residue at A37 (P = 0.0492)

MVP

0.17

MPC

1.6

ClinPred

0.28

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.12

gMVP

0.54

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over