19-5047472-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015015.3(KDM4B):c.433-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,598,600 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: KDM4B NM_015015.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008806
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-5047472-A-G is Benign according to our data. Variant chr19-5047472-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 711529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-5047472-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (346/152200) while in subpopulation NFE AF= 0.00405 (275/67976). AF 95% confidence interval is 0.00365. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 346 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM4B	NM_015015.3	c.433-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000159111.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM4B	ENST00000159111.9	c.433-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015015.3	P2

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 346 AN: 152082 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00405

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00210 AC: 510 AN: 242464 Hom.: 0 AF XY: 0.00212 AC XY: 279 AN XY: 131386

Gnomad AFR exome AF: 0.000562

Gnomad AMR exome AF: 0.000834

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000203

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00329 AC: 4754 AN: 1446400 Hom.: 11 Cov.: 32 AF XY: 0.00318 AC XY: 2279 AN XY: 717670

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00225

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.000382

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152200 Hom.: 2 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74426

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00405

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00261 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KDM4B: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Apr 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.33
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0020
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

LitVar

Other links and lift over

dbSNP: rs35556519; hg19: chr19-5047483;