12-318409-A-G

Position:

• chr12-318409-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (6875 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61193 hom.)
• Consequence: KDM5A NM_001042603.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.71

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 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=0.0027513206).
• BP6: Variant 12-318409-A-G is Benign according to our data. Variant chr12-318409-A-G is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
KDM5A	NM_001042603.3	c.2594T>C	p.Met865Thr	missense_variant	19/28	ENST00000399788.7	NP_001036068.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44937 AN: 151996 Hom.: 6858 Cov.: 32

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

GnomAD3 exomes AF: 0.312 AC: 77246 AN: 247256 Hom.: 12879 AF XY: 0.309 AC XY: 41465 AN XY: 134360

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 SAS exome AF: 0.345

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.: 35 AF XY: 0.284 AC XY: 206417 AN XY: 726978

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.351

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.519

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.296 AC: 44993 AN: 152114 Hom.: 6875 Cov.: 32 AF XY: 0.302 AC XY: 22486 AN XY: 74364

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.269

Alfa AF: 0.261 Hom.: 13713

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

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	GeneDx	Oct 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.054
Sift	Benign	0.50	T;T
Sift4G	Benign	0.52	T;.
Polyphen		0.0010	B;.
Vest4		0.14
MPC		0.21
ClinPred		0.012	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.23

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: rs11062385; hg19: chr12-427575; COSMIC: COSV66991468; COSMIC: COSV66991468;