19-35718040-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014727.3(KMT2B):c.22G>A(p.Gly8Ser) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26855344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.22G>A	p.Gly8Ser	missense_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.22G>A	p.Gly8Ser	missense_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.22G>A	p.Gly8Ser	missense_variant	1/37			A2
KMT2B	ENST00000692961.1	c.22G>A	p.Gly8Ser	missense_variant, NMD_transcript_variant	1/36
KMT2B	ENST00000687718.1	c.22G>A	p.Gly8Ser	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 838918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 388012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2B protein function. This variant has not been reported in the literature in individuals affected with KMT2B-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 8 of the KMT2B protein (p.Gly8Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	26
Dann	Benign	0.93
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.64	D;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		0.19	B
Vest4		0.27
MutPred		0.11		Gain of glycosylation at G8 (P = 0.0085);
MVP		0.40
ClinPred		0.35	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.094
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1969021050; hg19: chr19-36208942;