rs80132640

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.12028T>C(p.Ser4010Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,613,664 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 74 hom., cov: 33)

Exomes 𝑓: 0.028 ( 670 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.97

Publications

21 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025769174).

BP6

Variant 12-49032677-A-G is Benign according to our data. Variant chr12-49032677-A-G is described in ClinVar as [Benign]. Clinvar id is 94154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0245 (3723/152154) while in subpopulation NFE AF = 0.0348 (2366/67972). AF 95% confidence interval is 0.0336. There are 74 homozygotes in GnomAd4. There are 1831 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3723 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.12028T>C	p.Ser4010Pro	missense_variant	Exon 40 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.12028T>C	p.Ser4010Pro	missense_variant	Exon 40 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3723

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00452

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0542

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0348

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0263

AC:

6520

AN:

248348

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.00396

Gnomad AMR exome

AF:

0.0171

Gnomad ASJ exome

AF:

0.0210

Gnomad EAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.0325

Gnomad OTH exome

AF:

0.0295

GnomAD4 exome

AF:

0.0279

AC:

40721

AN:

1461510

Hom.:

670

Cov.:

AF XY:

0.0278

AC XY:

20239

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00388

AC:

130

AN:

33480

American (AMR)

AF:

0.0174

AC:

776

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0221

AC:

577

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0261

AC:

2250

AN:

86206

European-Finnish (FIN)

AF:

0.0464

AC:

2477

AN:

53386

Middle Eastern (MID)

AF:

0.0269

AC:

155

AN:

5768

European-Non Finnish (NFE)

AF:

0.0295

AC:

32777

AN:

1111790

Other (OTH)

AF:

0.0261

AC:

1573

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2784

5568

8351

11135

13919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0245

AC:

3723

AN:

152154

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

1831

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41502

American (AMR)

AF:

0.0213

AC:

325

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4822

European-Finnish (FIN)

AF:

0.0542

AC:

575

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0348

AC:

2366

AN:

67972

Other (OTH)

AF:

0.0227

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

191

382

574

765

956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0295

Hom.:

261

Bravo

AF:

0.0199

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0288

AC:

111

ESP6500AA

AF:

0.00455

AC:

ESP6500EA

AF:

0.0300

AC:

254

ExAC

AF:

0.0264

AC:

3200

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0324

EpiControl

AF:

0.0323

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Dec 31, 2014

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 07, 2016

Eurofins Ntd Llc (ga)

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

May 14, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.055

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

2.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.27

MPC

0.19

ClinPred

0.048

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.70

Mutation Taster

=98/2

polymorphism (auto)

(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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rs80132640

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