Genetic Variant NM_015015.3:c.-109+8503C>T (chr19-4977733-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.82

Publications

6 publications found

Variant links:

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

KDM4B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4B	NM_015015.3 link	c.-109+8503C>T		intron_variant	Intron 1 of 22	ENST00000159111.9	NP_055830.1	O94953A0A0C4DFL8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM4B	ENST00000159111.9 link	c.-109+8503C>T	intron_variant	Intron 1 of 22	1	NM_015015.3	ENSP00000159111.3	A0A0C4DFL8
KDM4B	ENST00000381759.8 link	c.-109+8503C>T	intron_variant	Intron 1 of 11	1		ENSP00000371178.3	O94953-2
KDM4B	ENST00000611640.4 link	c.-109+8503C>T	intron_variant	Intron 1 of 23	5		ENSP00000480642.1	F5GX28
KDM4B	ENST00000588337.5 link	c.-26+8503C>T	intron_variant	Intron 1 of 3	5		ENSP00000468514.1	K7ES23

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38722

AN:

151894

Hom.:

6316

Cov.:

show subpopulations

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.:

AF XY:

0.264

AC XY:

19617

AN XY:

74270

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.299

AC:

20329

AN:

67948

Other (OTH)

AF:

0.258

AC:

545

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1348

2695

4043

5390

6738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.13

(source)

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)

(source)

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

Publications

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NM_015015.3:c.-109+8503C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over