1-202764070-G-C

Variant names:

• chr1-202764070-G-C
• rs375695605
• NM_006618.5:c.787C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_006618.5(KDM5B):​c.787C>G​(p.Pro263Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. P263S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KDM5B NM_006618.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-202764070-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 560602.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07278055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5B	NM_006618.5	c.787C>G	p.Pro263Ala	missense_variant	Exon 6 of 27	ENST00000367265.9	NP_006609.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5B	ENST00000367265.9	c.787C>G	p.Pro263Ala	missense_variant	Exon 6 of 27	1	NM_006618.5	ENSP00000356234.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.017	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.41	N;.;.;.;.;.;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.27	N;.;N;.;.;.;.;.;N
REVEL	Benign	0.19
Sift	Benign	0.73	T;.;T;.;.;.;.;.;T
Sift4G	Benign	0.51	T;.;T;.;.;.;.;.;T
Polyphen		0.0	B;.;B;.;.;.;.;.;.
Vest4		0.12
MVP		0.47
MPC		0.66
ClinPred		0.082	T
GERP RS		3.8
Varity_R		0.029
gMVP		0.21
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs375695605; hg19: chr1-202733198;