19-5022593-T-C

Variant names:

• chr19-5022593-T-C
• rs263063
• NM_015015.3:c.-26+6254T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015015.3(KDM4B):​c.-26+6254T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 152,264 control chromosomes in the GnomAD database, including 64,005 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.92 (64005 hom., cov: 32)
• Consequence: KDM4B NM_015015.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.09
• Publications: 9 publications found

Genes affected

KDM4B (HGNC:29136): (lysine demethylase 4B) Enables histone H3-methyl-lysine-36 demethylase activity and histone H3-methyl-lysine-9 demethylase activity. Involved in histone H3-K36 demethylation and histone H3-K9 demethylation. Located in cytosol and nucleoplasm. Implicated in autosomal dominant non-syndromic intellectual disability; breast cancer; colorectal cancer; malignant peripheral nerve sheath tumor; and stomach cancer. Biomarker of several diseases, including alopecia areata; lung cancer; medulloblastoma; prostate cancer; and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

KDM4B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Illumina
• intellectual developmental disorder, autosomal dominant 65

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015015.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4B	NM_015015.3	MANE Select	c.-26+6254T>C		intron	N/A	NP_055830.1
	KDM4B	NM_001411148.1		c.-26+6254T>C		intron	N/A	NP_001398077.1
	KDM4B	NM_001370093.1		c.-26+6254T>C		intron	N/A	NP_001357022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4B	ENST00000159111.9	TSL:1 MANE Select	c.-26+6254T>C		intron	N/A	ENSP00000159111.3
	KDM4B	ENST00000536461.6	TSL:1	c.-26+6254T>C		intron	N/A	ENSP00000440495.1
	KDM4B	ENST00000381759.8	TSL:1	c.-26+6254T>C		intron	N/A	ENSP00000371178.3

Frequencies

GnomAD3 genomes AF: 0.916 AC: 139356 AN: 152146 Hom.: 63952 Cov.: 32

Gnomad AFR AF: 0.962

Gnomad AMI AF: 0.935

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.915

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.916 AC: 139463 AN: 152264 Hom.: 64005 Cov.: 32 AF XY: 0.915 AC XY: 68100 AN XY: 74446

African (AFR) AF: 0.962 AC: 39965 AN: 41564

American (AMR) AF: 0.852 AC: 13027 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 3176 AN: 3472

East Asian (EAS) AF: 0.789 AC: 4080 AN: 5172

South Asian (SAS) AF: 0.871 AC: 4196 AN: 4820

European-Finnish (FIN) AF: 0.929 AC: 9854 AN: 10604

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.913 AC: 62112 AN: 68022

Other (OTH) AF: 0.916 AC: 1938 AN: 2116

Alfa AF: 0.911 Hom.: 238699

Bravo AF: 0.912

Asia WGS AF: 0.855 AC: 2975 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.41
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs263063; hg19: chr19-5022604;