rs201623566

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003482.4(KMT2D):c.3392C>T(p.Pro1131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,752 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. P1131R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6O:1

Conservation

PhyloP100: 2.12

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048351347).

BP6

Variant 12-49050196-G-A is Benign according to our data. Variant chr12-49050196-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134672. Variant chr12-49050196-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134672. Variant chr12-49050196-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134672. Variant chr12-49050196-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134672. Variant chr12-49050196-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134672.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (167/152252) while in subpopulation NFE AF = 0.00119 (81/68018). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.3392C>T	p.Pro1131Leu	missense_variant	Exon 12 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KMT2D	ENST00000301067.12 link	c.3392C>T	p.Pro1131Leu	missense_variant	Exon 12 of 55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 link	c.3392C>T	p.Pro1131Leu	missense_variant	Exon 12 of 56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 link	c.3392C>T	p.Pro1131Leu	missense_variant	Exon 11 of 54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 link	c.3392C>T	p.Pro1131Leu	missense_variant	Exon 11 of 54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00116

AC:

288

AN:

247644

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.000266

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00629

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00104

AC:

1525

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

738

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00665

AC:

354

AN:

53232

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000987

AC:

1097

AN:

1111842

Other (OTH)

AF:

0.000745

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00110

AC:

167

AN:

152252

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41550

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000897

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000609

AC:

ExAC

AF:

0.00129

AC:

156

EpiCase

AF:

0.000327

EpiControl

AF:

0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: PP2, BP4, BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 30459467, 24633898) -

Kabuki syndrome 1

Uncertain:3

Sep 01, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KMT2D c.3392C>T; p.Pro1131Leu variant (rs201623566) is reported in the literature in individuals affected with Kabuki Syndrome (Micale 2014 and Faundes 2019). This variant is found in the Finnish European population with an allele frequency of 0.7% (identified on 164/24,936 alleles, including 1 homozygote) in the Genome Aggregation Database. The proline at codon 1131 is weakly conserved, and computational analyses (SIFT:damaging, PolyPhen-2:benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Pro1131Leu variant is uncertain at this time. Pathogenic variants in KMT2D are associated with autosomal dominant Kabuki syndrome 1 (MIM: 147920). References: Micale et al. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50. Faundes et al. A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population. J Hum Genet. 2019 Feb;64(2):161-170. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -

Kabuki syndrome

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KMT2D-related disorder

Benign:1

Mar 25, 2019

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). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.043

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

PhyloP100

2.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.30

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Polyphen

0.20

Vest4

0.73

MVP

0.093

MPC

0.28

ClinPred

0.038

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.089

gMVP

0.10

Mutation Taster

=87/13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over