Genetic Variant KMT2B:p.Ala27Ser (chr19-35718097-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014727.3(KMT2B):c.79G>T(p.Ala27Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A27V) has been classified 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: -0.454

Publications

0 publications found

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 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)

KMT2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07312134).

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.79G>T	p.Ala27Ser	missense	Exon 1 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.79G>T	p.Ala27Ser	missense	Exon 1 of 37	ENSP00000398837.2	Q9UMN6
KMT2B	ENST00000673918.2		c.79G>T	p.Ala27Ser	missense	Exon 1 of 37	ENSP00000501283.1	A0A669KBI7
KMT2B	ENST00000687718.1		n.79G>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000510535.1	A0A8I5KWP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

843028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

390518

African (AFR)

AF:

0.00

AC:

AN:

15932

American (AMR)

AF:

0.00

AC:

AN:

1360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5348

East Asian (EAS)

AF:

0.00

AC:

AN:

3946

South Asian (SAS)

AF:

0.00

AC:

AN:

17368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

768306

Other (OTH)

AF:

0.00

AC:

AN:

27872

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.022

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

-0.45

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.36

REVEL

Benign

0.079

Sift

Benign

0.55

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.10

MutPred

0.27

Gain of phosphorylation at A27 (P = 4e-04)

MVP

0.41

ClinPred

0.026

GERP RS

-1.1

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.076

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over