12-318409-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042603.3(KDM5A):c.2594T>C(p.Met865Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,613,294 control chromosomes in the GnomAD database, including 68,068 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6875 hom., cov: 32)

Exomes 𝑓: 0.28 ( 61193 hom. )

Consequence

KDM5A
NM_001042603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.71

Publications

50 publications found

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 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
neurodevelopmental disorder
Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics, G2P
El Hayek-Chahrour neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KDM5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027513206).

BP6

Variant 12-318409-A-G is Benign according to our data. Variant chr12-318409-A-G is described in ClinVar as Benign. ClinVar VariationId is 1255235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5A	NM_001042603.3 link	c.2594T>C	p.Met865Thr	missense_variant	Exon 19 of 28	ENST00000399788.7	NP_001036068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5A	ENST00000399788.7 link	c.2594T>C	p.Met865Thr	missense_variant	Exon 19 of 28	1	NM_001042603.3	ENSP00000382688.2
KDM5A	ENST00000544760.1 link	c.1451T>C	p.Met484Thr	missense_variant	Exon 10 of 13	2		ENSP00000440622.1

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44937

AN:

151996

Hom.:

6858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.317

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.272

GnomAD2 exomes

AF:

0.312

AC:

77246

AN:

247256

AF XY:

0.309

show subpopulations

Gnomad AFR exome

AF:

0.322

Gnomad AMR exome

AF:

0.357

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.500

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.284

AC:

414309

AN:

1461180

Hom.:

61193

Cov.:

AF XY:

0.284

AC XY:

206417

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.321

AC:

10747

AN:

33462

American (AMR)

AF:

0.351

AC:

15688

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

6542

AN:

26136

East Asian (EAS)

AF:

0.519

AC:

20615

AN:

39696

South Asian (SAS)

AF:

0.343

AC:

29596

AN:

86240

European-Finnish (FIN)

AF:

0.342

AC:

18276

AN:

53416

Middle Eastern (MID)

AF:

0.251

AC:

1448

AN:

5768

European-Non Finnish (NFE)

AF:

0.264

AC:

293627

AN:

1111364

Other (OTH)

AF:

0.294

AC:

17770

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

15371

30742

46112

61483

76854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10190

20380

30570

40760

50950

<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

AF:

0.296

AC:

44993

AN:

152114

Hom.:

6875

Cov.:

AF XY:

0.302

AC XY:

22486

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.318

AC:

13186

AN:

41498

American (AMR)

AF:

0.303

AC:

4622

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3470

East Asian (EAS)

AF:

0.510

AC:

2636

AN:

5170

South Asian (SAS)

AF:

0.364

AC:

1753

AN:

4818

European-Finnish (FIN)

AF:

0.345

AC:

3647

AN:

10576

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17510

AN:

67996

Other (OTH)

AF:

0.269

AC:

569

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1603

3205

4808

6410

8013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.268

Hom.:

22021

Bravo

AF:

0.296

TwinsUK

AF:

0.261

AC:

968

ALSPAC

AF:

0.252

AC:

971

ESP6500AA

AF:

0.317

AC:

1180

ESP6500EA

AF:

0.254

AC:

2085

ExAC

AF:

0.310

AC:

37465

Asia WGS

AF:

0.426

AC:

1478

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.041

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;.

PhyloP100

2.7

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.72

N;N

REVEL

Benign

0.054

Sift

Benign

0.50

T;T

Sift4G

Benign

0.52

T;.

Vest4

0.14

ClinPred

0.012

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.23

Mutation Taster

=99/1

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over