dbSNP rs1969021050: KMT2B:p.Gly8Ser (chr19-35718040-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
KMT2B	NM_014727.3 link	c.22G>A	p.Gly8Ser	missense_variant	Exon 1 of 37	ENST00000420124.4	NP_055542.1	Q9UMN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KMT2B	ENST00000420124.4 link	c.22G>A	p.Gly8Ser	missense_variant	Exon 1 of 37	1	NM_014727.3	ENSP00000398837.2	Q9UMN6
KMT2B	ENST00000673918.2 link	c.22G>A	p.Gly8Ser	missense_variant	Exon 1 of 37			ENSP00000501283.1	A0A669KBI7
KMT2B	ENST00000687718.1 link	n.22G>A		non_coding_transcript_exon_variant	Exon 1 of 3			ENSP00000510535.1	A0A8I5KWP7
KMT2B	ENST00000692961.1 link	n.22G>A		non_coding_transcript_exon_variant	Exon 1 of 36			ENSP00000509289.1	A0A8I5KPK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

838918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 variant has not been reported in the literature in individuals affected with KMT2B-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Benign

0.93

DEOGEN2

Benign

0.025

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.29

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

0.19

Vest4

0.27

MutPred

0.11

Gain of glycosylation at G8 (P = 0.0085);

MVP

0.40

ClinPred

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over