1-202729753-T-A

Variant names:

• chr1-202729753-T-A
• rs775686902
• NM_006618.5:c.4451A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006618.5(KDM5B):​c.4451A>T​(p.Asp1484Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1484H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KDM5B NM_006618.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26361328).

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.4451A>T	p.Asp1484Val	missense	Exon 26 of 27	NP_006609.3
	KDM5B	NM_001314042.2		c.4559A>T	p.Asp1520Val	missense	Exon 27 of 28	NP_001300971.1	Q9UGL1-2
	KDM5B	NM_001399817.1		c.4436A>T	p.Asp1479Val	missense	Exon 26 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.4451A>T	p.Asp1484Val	missense	Exon 26 of 27	ENSP00000356234.3	Q9UGL1-1
	KDM5B	ENST00000367264.7	TSL:1	c.4559A>T	p.Asp1520Val	missense	Exon 27 of 28	ENSP00000356233.2	Q9UGL1-2
	KDM5B	ENST00000472822.6	TSL:1	n.1457A>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.059	T
Sift4G	Benign	0.18	T
Polyphen		0.52	P
Vest4		0.67
MutPred		0.36		Gain of sheet (P = 0.0125)
MVP		0.42
MPC		0.43
ClinPred		0.44	T
GERP RS		5.7
PromoterAI		0.0012	Neutral
Varity_R		0.22
gMVP		0.39
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

dbSNP: rs775686902; hg19: chr1-202698881;