1-202729822-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_006618.5(KDM5B):c.4382G>A(p.Arg1461His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: KDM5B NM_006618.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03415835).
• BP6: Variant 1-202729822-C-T is Benign according to our data. Variant chr1-202729822-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2317830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-202729822-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5B	NM_006618.5	c.4382G>A	p.Arg1461His	missense_variant	26/27	ENST00000367265.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5B	ENST00000367265.9	c.4382G>A	p.Arg1461His	missense_variant	26/27	1	NM_006618.5	P4

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000402 AC: 101 AN: 251474 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000624

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000468 AC: 684 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000436 AC XY: 317 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.000531

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74338

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000566 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KDM5B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

This variant is classified as likely 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	Benign	0.068
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T;.;.;.;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;.;N;.;.;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.019	D;.;D;.;.;.;.;.
Sift4G	Benign	0.11	T;.;T;.;.;.;.;.
Polyphen		0.0040	B;.;B;.;.;.;.;.
Vest4		0.17
MVP		0.48
MPC		0.27
ClinPred		0.037	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139343230; hg19: chr1-202698950; COSMIC: COSV99350490; COSMIC: COSV99350490;