12-292952-T-A

Position:

chr12-292952-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042603.3(KDM5A):c.4673A>T(p.Glu1558Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,554 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 13 hom. )

Consequence

KDM5A
NM_001042603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

KDM5A (HGNC:9886): (lysine demethylase 5A) This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

KDM5A links:

KDM5A (HGNC:):

KDM5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM5A. . Gene score misZ 2.2471 (greater than the threshold 3.09). Trascript score misZ 3.5946 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.007874429).

BP6

Variant 12-292952-T-A is Benign according to our data. Variant chr12-292952-T-A is described in ClinVar as [Benign]. Clinvar id is 713353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-292952-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00158 (2305/1461198) while in subpopulation AFR AF= 0.017 (568/33424). AF 95% confidence interval is 0.0158. There are 13 homozygotes in gnomad4_exome. There are 1096 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 802 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5A	NM_001042603.3 linkuse as main transcript	c.4673A>T	p.Glu1558Val	missense_variant	27/28	ENST00000399788.7	NP_001036068.1	P29375-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5A	ENST00000399788.7 linkuse as main transcript	c.4673A>T	p.Glu1558Val	missense_variant	27/28	1	NM_001042603.3	ENSP00000382688.2		P29375-1
KDM5A	ENST00000540838.1 linkuse as main transcript	n.-27A>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00526

AC:

801

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00254

AC:

632

AN:

248968

Hom.:

AF XY:

0.00225

AC XY:

304

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00325

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000814

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00158

AC:

2305

AN:

1461198

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1096

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.00334

Gnomad4 ASJ exome

AF:

0.0154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000837

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00526

AC:

802

AN:

152356

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

382

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00264

Hom.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.00147

AC:

ExAC

AF:

0.00226

AC:

273

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2018	- -

KDM5A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as 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

0.50

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0079

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.48

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.46

MVP

0.57

MPC

0.76

ClinPred

0.016

GERP RS

5.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.18

gMVP

0.25

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