1-202729066-A-T

Variant names:

• chr1-202729066-A-T
• NM_006618.5:c.4605T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_006618.5(KDM5B):​c.4605T>A​(p.Cys1535*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM5B NM_006618.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 65

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00647 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006618.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5B	NM_006618.5	MANE Select	c.4605T>A	p.Cys1535*	stop_gained	Exon 27 of 27	NP_006609.3
	KDM5B	NM_001314042.2		c.4713T>A	p.Cys1571*	stop_gained	Exon 28 of 28	NP_001300971.1	Q9UGL1-2
	KDM5B	NM_001399817.1		c.4590T>A	p.Cys1530*	stop_gained	Exon 27 of 27	NP_001386746.1	A0A3B3IS40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5B	ENST00000367265.9	TSL:1 MANE Select	c.4605T>A	p.Cys1535*	stop_gained	Exon 27 of 27	ENSP00000356234.3	Q9UGL1-1
	KDM5B	ENST00000367264.7	TSL:1	c.4713T>A	p.Cys1571*	stop_gained	Exon 28 of 28	ENSP00000356233.2	Q9UGL1-2
	KDM5B	ENST00000472822.6	TSL:1	n.2144T>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal recessive 65 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.0
Vest4		0.61
GERP RS		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=31/169	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-202698194;