rs199547661

Variant names:

Variant summary

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

The NM_003482.4(KMT2D):c.8774C>T(p.Ala2925Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,538 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2925A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: 1.82

Publications

9 publications found

Variant links:

COSMIC-nc: COSV56409053

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=0.0050002933).

BP6

Variant 12-49038582-G-A is Benign according to our data. Variant chr12-49038582-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94260.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00217 (330/152280) while in subpopulation AFR AF = 0.00267 (111/41552). AF 95% confidence interval is 0.00227. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.8774C>T	p.Ala2925Val	missense_variant	Exon 35 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.8774C>T	p.Ala2925Val	missense_variant	Exon 35 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

329

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00166

AC:

410

AN:

247666

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00295

Gnomad FIN exome

AF:

0.00237

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00213

AC:

3107

AN:

1460258

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1489

AN XY:

726222

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33468

American (AMR)

AF:

0.000403

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00146

AC:

AN:

39674

South Asian (SAS)

AF:

0.000383

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00228

AC:

120

AN:

52692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00240

AC:

2662

AN:

1111224

Other (OTH)

AF:

0.00186

AC:

112

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

211

421

632

842

1053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00217

AC:

330

AN:

152280

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41552

American (AMR)

AF:

0.000719

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00250

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68022

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00204

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00187

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00171

AC:

207

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Jun 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BS1 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30459467, 30107592, 28389907, 29627316, 28440294) -

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

- -

Kabuki syndrome 1

Uncertain:1

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.044

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.34

PhyloP100

1.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Uncertain

0.0040

Polyphen

0.0040

Vest4

0.087

MVP

0.31

MPC

0.16

ClinPred

0.011

GERP RS

4.4

PromoterAI

-0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.088

gMVP

0.18

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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