Variant chr7-102457497-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000292566.4(ALKBH4):c.806C>A(p.Thr269Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ALKBH4
ENST00000292566.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.26

Variant links:

Genes affected

ALKBH4 (HGNC:21900): (alkB homolog 4, lysine demethylase) Enables 2-oxoglutarate-dependent dioxygenase activity and actin binding activity. Involved in actomyosin structure organization; cleavage furrow ingression; and protein demethylation. Located in contractile ring and midbody. [provided by Alliance of Genome Resources, Apr 2022]

ALKBH4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKBH4	NM_017621.4 linkuse as main transcript	c.806C>A	p.Thr269Asn	missense_variant	3/3	ENST00000292566.4	NP_060091.1	Q9NXW9-1
ALKBH4	XM_005250464.4 linkuse as main transcript	c.587C>A	p.Thr196Asn	missense_variant	3/3		XP_005250521.1	Q9NXW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALKBH4	ENST00000292566.4 linkuse as main transcript	c.806C>A	p.Thr269Asn	missense_variant	3/3	1	NM_017621.4	ENSP00000292566.3	Q9NXW9-1
ALKBH4	ENST00000490528.1 linkuse as main transcript	n.*586C>A		non_coding_transcript_exon_variant	3/3	2		ENSP00000420362.1	Q9NXW9-2
ALKBH4	ENST00000490528.1 linkuse as main transcript	n.*586C>A		3_prime_UTR_variant	3/3	2		ENSP00000420362.1	Q9NXW9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249930

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135534

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

May 31, 2023

The c.806C>A (p.T269N) alteration is located in exon 3 (coding exon 3) of the ALKBH4 gene. This alteration results from a C to A substitution at nucleotide position 806, causing the threonine (T) at amino acid position 269 to be replaced by an asparagine (N). 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

Pathogenic

0.81

BayesDel_addAF

Benign

0.0052

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.0096

MutationAssessor

Pathogenic

3.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.90

MutPred

0.75

Gain of helix (P = 0.0854);

MVP

0.71

MPC

0.96

ClinPred

1.0

GERP RS

5.1

Varity_R

0.69

gMVP

0.96

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