rs138399600

Positions:

• chr19-35719453-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014727.3(KMT2B):​c.364-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,565,752 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (126 hom.)
• Consequence: KMT2B NM_014727.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0540

Genes affected

KMT2B (HGNC:15840): (lysine methyltransferase 2B) This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-35719453-C-T is Benign according to our data. Variant chr19-35719453-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2B	NM_014727.3	c.364-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000420124.4	NP_055542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2B	ENST00000420124.4	c.364-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014727.3	ENSP00000398837	P2
KMT2B	ENST00000673918.2	c.364-16C>T		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000501283	A2
KMT2B	ENST00000687718.1	c.364-331C>T		intron_variant, NMD_transcript_variant				ENSP00000510535
KMT2B	ENST00000692961.1	c.364-16C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000509289

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 733 AN: 152176 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.0124 AC: 2225 AN: 178846 Hom.: 91 AF XY: 0.00950 AC XY: 911 AN XY: 95890

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.0792

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00234 AC: 3307 AN: 1413458 Hom.: 126 Cov.: 30 AF XY: 0.00203 AC XY: 1422 AN XY: 699236

Gnomad4 AFR exome AF: 0.000560

Gnomad4 AMR exome AF: 0.0778

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.0000902

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152294 Hom.: 22 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74470

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.0429

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00926

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138399600; hg19: chr19-36210355;