12-49051743-G-T

Position:

chr12-49051743-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_003482.4(KMT2D):c.1940C>A(p.Pro647Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,585,578 control chromosomes in the GnomAD database, including 4 homozygotes. 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).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00073 ( 4 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

Conservation

PhyloP100: 1.50

Variant links:

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2D. . Gene score misZ 3.7288 (greater than the threshold 3.09). Trascript score misZ 4.6964 (greater than threshold 3.09). GenCC has associacion of gene with Kabuki syndrome, branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, Kabuki syndrome 1, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0853588).

BS2

High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.1940C>A	p.Pro647Gln	missense_variant	11/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.1940C>A	p.Pro647Gln	missense_variant	11/55	5	NM_003482.4	ENSP00000301067	A2	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.1940C>A	p.Pro647Gln	missense_variant	11/56			ENSP00000506726	P4
KMT2D	ENST00000685166.1 linkuse as main transcript	c.1940C>A	p.Pro647Gln	missense_variant	10/54			ENSP00000509386	A2	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.1940C>A	p.Pro647Gln	missense_variant	10/54			ENSP00000509666	A2

Frequencies

GnomAD3 genomes

AF:

0.000496

AC:

AN:

149314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00153

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000426

Gnomad FIN

AF:

0.000289

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000536

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000465

AC:

114

AN:

245350

Hom.:

AF XY:

0.000542

AC XY:

AN XY:

132962

show subpopulations

Gnomad AFR exome

AF:

0.000326

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000895

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000671

GnomAD4 exome

AF:

0.000734

AC:

1054

AN:

1436144

Hom.:

Cov.:

AF XY:

0.000759

AC XY:

542

AN XY:

714306

show subpopulations

Gnomad4 AFR exome

AF:

0.000363

Gnomad4 AMR exome

AF:

0.000315

Gnomad4 ASJ exome

AF:

0.000117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000993

Gnomad4 FIN exome

AF:

0.000416

Gnomad4 NFE exome

AF:

0.000787

Gnomad4 OTH exome

AF:

0.000893

GnomAD4 genome

AF:

0.000502

AC:

AN:

149434

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

AN XY:

73010

show subpopulations

Gnomad4 AFR

AF:

0.000247

Gnomad4 AMR

AF:

0.00153

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000639

Gnomad4 FIN

AF:

0.000289

Gnomad4 NFE

AF:

0.000536

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000601

Hom.:

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.000594

AC:

ExAC

AF:

0.000405

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KMT2D: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29778030, 21607748, 26092435, 23320472, 30459467, 30107592) -

Kabuki syndrome 1

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Genetic and Metabolic Disease Program, Children's Medical Center Research Institute, UT Southwestern Medical Center at Dallas	Feb 01, 2017	This variant is identified in a male proband presenting with clinical features of Kabuki syndrome. This variant is maternally inherited. The mother shares some clinical features with the son and she has recently been diagnosed with chronic myelogenous leukemia (CML). -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Kabuki syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

KMT2D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.044

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.90

REVEL

Uncertain

0.44

Sift

Benign

0.11

Polyphen

0.85

Vest4

0.39

MVP

0.82

MPC

0.17

ClinPred

0.017

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.043

gMVP

0.33

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