19-4977733-C-T

Variant names:

• chr19-4977733-C-T
• rs753842
• NM_015015.3:c.-109+8503C>T

Variant summary

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

The NM_015015.3(KDM4B):​c.-109+8503C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,012 control chromosomes in the GnomAD database, including 6,316 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 0.25 (6316 hom., cov: 32)
• Consequence: KDM4B NM_015015.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 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.-109+8503C>T		intron	N/A	NP_055830.1
	KDM4B	NM_001370093.1		c.-109+8503C>T		intron	N/A	NP_001357022.1
	KDM4B	NM_001370094.1		c.-109+8503C>T		intron	N/A	NP_001357023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4B	ENST00000159111.9	TSL:1 MANE Select	c.-109+8503C>T		intron	N/A	ENSP00000159111.3
	KDM4B	ENST00000381759.8	TSL:1	c.-109+8503C>T		intron	N/A	ENSP00000371178.3
	KDM4B	ENST00000611640.4	TSL:5	c.-109+8503C>T		intron	N/A	ENSP00000480642.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38722 AN: 151894 Hom.: 6316 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.253

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

GnomAD4 genome AF: 0.255 AC: 38716 AN: 152012 Hom.: 6316 Cov.: 32 AF XY: 0.264 AC XY: 19617 AN XY: 74270

African (AFR) AF: 0.0823 AC: 3416 AN: 41510

American (AMR) AF: 0.227 AC: 3469 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3470

East Asian (EAS) AF: 0.689 AC: 3555 AN: 5158

South Asian (SAS) AF: 0.322 AC: 1549 AN: 4818

European-Finnish (FIN) AF: 0.433 AC: 4560 AN: 10526

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20329 AN: 67948

Other (OTH) AF: 0.258 AC: 545 AN: 2114

Alfa AF: 0.288 Hom.: 3504

Bravo AF: 0.236

Asia WGS AF: 0.442 AC: 1536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.48
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs753842; hg19: chr19-4977744;