Genetic Variant KDM4B:c.781-1731C>T (chr19-5080636-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.781-1731C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 152,276 control chromosomes in the GnomAD database, including 894 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 0.093 ( 893 hom., cov: 33)

Exomes 𝑓: 0.22 ( 1 hom. )

Consequence

KDM4B
NM_015015.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.58

Publications

7 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), ClinGen
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=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.235 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM4B	NM_015015.3	MANE Select	c.781-1731C>T	intron	N/A	NP_055830.1	A0A0C4DFL8
KDM4B	NM_001411148.1		c.781-1731C>T	intron	N/A	NP_001398077.1	F5GX28
KDM4B	NM_001370093.1		c.781-1731C>T	intron	N/A	NP_001357022.1	O94953-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM4B	ENST00000159111.9	TSL:1 MANE Select	c.781-1731C>T	intron	N/A	ENSP00000159111.3	A0A0C4DFL8
KDM4B	ENST00000536461.6	TSL:1	c.781-1731C>T	intron	N/A	ENSP00000440495.1	F5GX28
KDM4B	ENST00000381759.8	TSL:1	c.781-1731C>T	intron	N/A	ENSP00000371178.3	O94953-2

Frequencies

GnomAD3 genomes

AF:

0.0929

AC:

14132

AN:

152140

Hom.:

886

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.0845

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0919

Gnomad OTH

AF:

0.0903

GnomAD4 exome

AF:

0.222

AC:

AN:

Hom.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.700

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0929

AC:

14143

AN:

152258

Hom.:

893

Cov.:

AF XY:

0.0951

AC XY:

7077

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0379

AC:

1576

AN:

41568

American (AMR)

AF:

0.184

AC:

2815

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

368

AN:

3466

East Asian (EAS)

AF:

0.246

AC:

1274

AN:

5172

South Asian (SAS)

AF:

0.132

AC:

638

AN:

4824

European-Finnish (FIN)

AF:

0.0845

AC:

896

AN:

10602

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0919

AC:

6251

AN:

68010

Other (OTH)

AF:

0.0893

AC:

189

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

634

1268

1903

2537

3171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0798

Hom.:

592

Bravo

AF:

0.0999

Asia WGS

AF:

0.164

AC:

570

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.040

(source)

DANN

Benign

0.58

PhyloP100

-3.6

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over