1-202729710-A-T

Position:

chr1-202729710-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_006618.5(KDM5B):c.4494T>A(p.Asp1498Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,612,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

KDM5B
NM_006618.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.907

Variant links:

Genes affected

KDM5B (HGNC:18039): (lysine demethylase 5B) This gene encodes a lysine-specific histone demethylase that belongs to the jumonji/ARID domain-containing family of histone demethylases. The encoded protein is capable of demethylating tri-, di- and monomethylated lysine 4 of histone H3. This protein plays a role in the transcriptional repression or certain tumor suppressor genes and is upregulated in certain cancer cells. This protein may also play a role in genome stability and DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

KDM5B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07231936).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000227 (331/1460182) while in subpopulation MID AF= 0.00434 (25/5754). AF 95% confidence interval is 0.00302. There are 1 homozygotes in gnomad4_exome. There are 170 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5B	NM_006618.5 link	c.4494T>A	p.Asp1498Glu	missense_variant	26/27	ENST00000367265.9	NP_006609.3	Q9UGL1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5B	ENST00000367265.9 link	c.4494T>A	p.Asp1498Glu	missense_variant	26/27	1	NM_006618.5	ENSP00000356234.3		Q9UGL1-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000176

AC:

AN:

250128

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000227

AC:

331

AN:

1460182

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

726256

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000230

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000138

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2021

Unlikely to be causative of autosomal dominant KDM5B-related neurodevelopmental disorder (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.019

T;.;.;.;.;.;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;.;T;T;T;T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.072

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.55

N;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.1

N;.;.;N;.;.;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.28

T;.;.;T;.;.;.;.;.

Sift4G

Benign

0.75

T;.;.;T;.;.;.;.;.

Polyphen

0.011

B;.;.;B;.;.;.;.;.

Vest4

0.34

MutPred

0.44

Gain of catalytic residue at D1498 (P = 0.0934);.;Gain of catalytic residue at D1498 (P = 0.0934);.;.;Gain of catalytic residue at D1498 (P = 0.0934);.;.;.;

MVP

0.30

MPC

0.25

ClinPred

0.029

GERP RS

2.0

Varity_R

0.059

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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