rs372432644

chr19-35730035-C-Achr19-35730035-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014727.3(KMT2B):c.4986C>A(p.Phe1662Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F1662F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.746

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014727.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.4986C>A	p.Phe1662Leu	missense_variant	23/37	ENST00000420124.4
KMT2B	XM_011527561.3	c.4920C>A	p.Phe1640Leu	missense_variant	23/37
KMT2B	XM_011527562.3	c.4986C>A	p.Phe1662Leu	missense_variant	23/36
KMT2B	XM_047439787.1	c.4710C>A	p.Phe1570Leu	missense_variant	22/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.4986C>A	p.Phe1662Leu	missense_variant	23/37	1	NM_014727.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 28, childhood-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Apr 16, 2018

This variant is interpreted as a Uncertain Significance, for Dystonia 28, childhood-onset, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.70	P
Vest4		0.57
MutPred		0.74		Loss of loop (P = 0.0203);
MVP		0.84
ClinPred		0.90	D
GERP RS		2.0
Varity_R		0.11
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372432644; hg19: chr19-36220936;