19-35718121-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014727.3(KMT2B):c.103G>C(p.Gly35Arg) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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 2 ACMG points.

• 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.103G>C	p.Gly35Arg	missense_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.103G>C	p.Gly35Arg	missense_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.103G>C	p.Gly35Arg	missense_variant	1/37			A2
KMT2B	ENST00000692961.1	c.103G>C	p.Gly35Arg	missense_variant, NMD_transcript_variant	1/36
KMT2B	ENST00000687718.1	c.103G>C	p.Gly35Arg	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.103G>C (p.G35R) alteration is located in exon 1 (coding exon 1) of the KMT2B gene. This alteration results from a G to C substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.29	N
REVEL	Benign	0.28
Sift	Benign	0.31	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.35		Gain of methylation at G35 (P = 0.0037);
MVP		0.57
ClinPred		0.48	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36209023;