chr12-49051743-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P647T) has been classified as Likely benign.

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

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
Kabuki syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Kabuki syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

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

BP6

Variant 12-49051743-G-T is Benign according to our data. Variant chr12-49051743-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94196.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000502 (75/149434) while in subpopulation AMR AF = 0.00153 (23/15060). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAd4 at 75 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.1940C>A	p.Pro647Gln	missense	Exon 11 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.1940C>A	p.Pro647Gln	missense	Exon 11 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.1940C>A	p.Pro647Gln	missense	Exon 11 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.1940C>A	p.Pro647Gln	missense	Exon 10 of 54	ENSP00000509386.1

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

GnomAD2 exomes

AF:

0.000465

AC:

114

AN:

245350

AF XY:

0.000542

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 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

African (AFR)

AF:

0.000363

AC:

AN:

33048

American (AMR)

AF:

0.000315

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.000117

AC:

AN:

25690

East Asian (EAS)

AF:

0.00

AC:

AN:

39330

South Asian (SAS)

AF:

0.000993

AC:

AN:

85578

European-Finnish (FIN)

AF:

0.000416

AC:

AN:

52942

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.000787

AC:

858

AN:

1089972

Other (OTH)

AF:

0.000893

AC:

AN:

59374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000502

AC:

AN:

149434

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

AN XY:

73010

show subpopulations

African (AFR)

AF:

0.000247

AC:

AN:

40452

American (AMR)

AF:

0.00153

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.000639

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.000289

AC:

AN:

10392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000536

AC:

AN:

67126

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000604

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

Apr 24, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Jan 07, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BP4, BS1, BS2

Kabuki syndrome 1

Pathogenic:1Uncertain:1

Feb 01, 2017

Genetic and Metabolic Disease Program, Children's Medical Center Research Institute, UT Southwestern Medical Center at Dallas

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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).

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Kabuki syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D-related disorder

Benign:1

Aug 17, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

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

PhyloP100

1.5

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

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over