NM_014727.3:c.4545C>T

Variant names:

• chr19-35728145-C-T
• rs1057519284
• NM_014727.3:c.4545C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_014727.3(KMT2B):​c.4545C>T​(p.Tyr1515Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2B NM_014727.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 0 publications found

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]

KMT2B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with motor features

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dystonia 28, childhood-onset

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• intellectual developmental disorder, autosomal dominant 68

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014727.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	NM_014727.3	MANE Select	c.4545C>T	p.Tyr1515Tyr	synonymous	Exon 19 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.4545C>T	p.Tyr1515Tyr	synonymous	Exon 19 of 37	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.4479C>T	p.Tyr1493Tyr	synonymous	Exon 19 of 37	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000690290.1		c.510C>T	p.Tyr170Tyr	synonymous	Exon 5 of 5	ENSP00000510450.1	A0A8I5KWL4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717910

African (AFR) AF: 0.00 AC: 0 AN: 33068

American (AMR) AF: 0.00 AC: 0 AN: 42884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 38766

South Asian (SAS) AF: 0.00 AC: 0 AN: 83386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105066

Other (OTH) AF: 0.00 AC: 0 AN: 59848

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.7
DANN	Benign	0.55
PhyloP100		0.13

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: rs1057519284; hg19: chr19-36219046;