19-35720684-C-T

Position:

chr19-35720684-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_014727.3(KMT2B):c.1337C>T(p.Pro446Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,481,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P446P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KMT2B
NM_014727.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.130

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2602406).

BP6

Variant 19-35720684-C-T is Benign according to our data. Variant chr19-35720684-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548572.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000012 (16/1331192) while in subpopulation MID AF= 0.000574 (3/5222). AF 95% confidence interval is 0.000156. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 42. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3 linkuse as main transcript	c.1337C>T	p.Pro446Leu	missense_variant	3/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4 linkuse as main transcript	c.1337C>T	p.Pro446Leu	missense_variant	3/37	1	NM_014727.3	P2

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000352

AC:

AN:

85330

Hom.:

AF XY:

0.0000466

AC XY:

AN XY:

42918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000237

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1331192

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

650920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000500

Gnomad4 EAS exome

AF:

0.0000564

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000857

Gnomad4 OTH exome

AF:

0.0000182

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149956

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73074

show subpopulations

Gnomad4 AFR

AF:

0.0000247

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000875

Hom.:

ExAC

AF:

0.0000208

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dystonia 28, childhood-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.25

CADD

Benign

8.7

DANN

Benign

0.93

DEOGEN2

Benign

0.026

Eigen

Benign

0.025

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.43

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.26

MetaSVM

Uncertain

-0.0066

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.34

Sift

Benign

0.037

Sift4G

Uncertain

0.035

Polyphen

1.0

Vest4

0.29

MutPred

0.33

Loss of glycosylation at P446 (P = 0.0025);

MVP

0.39

ClinPred

0.22

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.20

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