12-49052257-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003482.4(KMT2D):c.1426G>A(p.Ala476Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,478,052 control chromosomes in the GnomAD database, including 3,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 1650 hom., cov: 30)

Exomes 𝑓: 0.011 ( 1610 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -2.15

Publications

20 publications found

Variant links:

COSMIC-nc: COSV56457249

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=0.004093617).

BP6

Variant 12-49052257-C-T is Benign according to our data. Variant chr12-49052257-C-T is described in ClinVar as Benign. ClinVar VariationId is 94174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.1426G>A	p.Ala476Thr	missense_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.1426G>A	p.Ala476Thr	missense_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes

AF:

0.0888

AC:

12313

AN:

138598

Hom.:

1636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0435

Gnomad ASJ

AF:

0.00431

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0670

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.0691

GnomAD2 exomes

AF:

0.0277

AC:

5707

AN:

205848

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.337

Gnomad AMR exome

AF:

0.0207

Gnomad ASJ exome

AF:

0.00406

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0107

AC:

14277

AN:

1339318

Hom.:

1610

Cov.:

AF XY:

0.00982

AC XY:

6494

AN XY:

661574

show subpopulations

African (AFR)

AF:

0.321

AC:

10078

AN:

31362

American (AMR)

AF:

0.0231

AC:

815

AN:

35212

Ashkenazi Jewish (ASJ)

AF:

0.00434

AC:

100

AN:

23040

East Asian (EAS)

AF:

0.00

AC:

AN:

32598

South Asian (SAS)

AF:

0.0167

AC:

1126

AN:

67330

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

49028

Middle Eastern (MID)

AF:

0.0222

AC:

118

AN:

5314

European-Non Finnish (NFE)

AF:

0.000737

AC:

767

AN:

1041316

Other (OTH)

AF:

0.0235

AC:

1272

AN:

54118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

667

1334

2001

2668

3335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.0892

AC:

12373

AN:

138734

Hom.:

1650

Cov.:

AF XY:

0.0860

AC XY:

5802

AN XY:

67490

show subpopulations

African (AFR)

AF:

0.301

AC:

11485

AN:

38110

American (AMR)

AF:

0.0434

AC:

599

AN:

13796

Ashkenazi Jewish (ASJ)

AF:

0.00431

AC:

AN:

3250

East Asian (EAS)

AF:

0.00

AC:

AN:

4312

South Asian (SAS)

AF:

0.0133

AC:

AN:

4120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9414

Middle Eastern (MID)

AF:

0.0652

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

62830

Other (OTH)

AF:

0.0684

AC:

129

AN:

1886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

428

857

1285

1714

2142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0262

Hom.:

1051

Bravo

AF:

0.0939

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.274

AC:

1173

ESP6500EA

AF:

0.00166

AC:

ExAC

AF:

0.0279

AC:

3386

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Mar 16, 2016

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

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

0.074

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.38

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.035

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-2.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.070

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Polyphen

0.015

Vest4

0.025

MPC

0.18

ClinPred

0.0028

GERP RS

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.042

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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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