12-295692-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042603.3(KDM5A):c.4336G>C(p.Glu1446Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,120 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (13 hom.)
• Consequence: KDM5A NM_001042603.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.60

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KDM5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.007984221).
• BP6: Variant 12-295692-C-G is Benign according to our data. Variant chr12-295692-C-G is described in ClinVar as [Benign]. Clinvar id is 776683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00663 (1010/152256) while in subpopulation AFR AF= 0.0231 (958/41526). AF 95% confidence interval is 0.0219. There are 15 homozygotes in gnomad4. There are 478 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1009 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5A	NM_001042603.3	c.4336G>C	p.Glu1446Gln	missense_variant	26/28	ENST00000399788.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5A	ENST00000399788.7	c.4336G>C	p.Glu1446Gln	missense_variant	26/28	1	NM_001042603.3	P1

Frequencies

GnomAD3 genomes AF: 0.00663 AC: 1009 AN: 152138 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00171 AC: 427 AN: 249426 Hom.: 4 AF XY: 0.00138 AC XY: 187 AN XY: 135308

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00107

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: 0.0000177

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000683 AC: 999 AN: 1461864 Hom.: 13 Cov.: 31 AF XY: 0.000579 AC XY: 421 AN XY: 727234

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152256 Hom.: 15 Cov.: 32 AF XY: 0.00642 AC XY: 478 AN XY: 74456

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00794

ESP6500AA AF: 0.0179 AC: 68

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

KDM5A-related disorder Benign:1

Benign, criteria provided, single submitter

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	0.39
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.77
MVP		0.65
MPC		0.24
ClinPred		0.026	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.39
gMVP		0.56

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

Other links and lift over

dbSNP: rs112579803; hg19: chr12-404858; COSMIC: COSV99060473; COSMIC: COSV99060473;