rs61942218

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003482.4(KMT2D):c.10671A>G(p.Pro3557Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,613,254 control chromosomes in the GnomAD database, including 3,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 174 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3093 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.90

Publications

6 publications found

Variant links:

COSMIC-nc: COSV56419845

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 12-49034136-T-C is Benign according to our data. Variant chr12-49034136-T-C is described in ClinVar as Benign. ClinVar VariationId is 94138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.10671A>G	p.Pro3557Pro	synonymous_variant	Exon 39 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.10671A>G	p.Pro3557Pro	synonymous_variant	Exon 39 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0423

AC:

6436

AN:

152154

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.0757

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0435

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0631

Gnomad OTH

AF:

0.0468

GnomAD2 exomes

AF:

0.0462

AC:

11489

AN:

248740

AF XY:

0.0463

show subpopulations

Gnomad AFR exome

AF:

0.00988

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.0826

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0451

Gnomad NFE exome

AF:

0.0655

Gnomad OTH exome

AF:

0.0630

GnomAD4 exome

AF:

0.0612

AC:

89441

AN:

1460982

Hom.:

3093

Cov.:

AF XY:

0.0599

AC XY:

43500

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.00995

AC:

333

AN:

33478

American (AMR)

AF:

0.0393

AC:

1757

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0798

AC:

2086

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0172

AC:

1480

AN:

86258

European-Finnish (FIN)

AF:

0.0458

AC:

2414

AN:

52706

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5768

European-Non Finnish (NFE)

AF:

0.0701

AC:

77887

AN:

1111850

Other (OTH)

AF:

0.0555

AC:

3351

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5171

10343

15514

20686

25857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2898

5796

8694

11592

14490

<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:

0.0423

AC:

6437

AN:

152272

Hom.:

174

Cov.:

AF XY:

0.0412

AC XY:

3066

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0118

AC:

491

AN:

41562

American (AMR)

AF:

0.0426

AC:

652

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0757

AC:

263

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.0130

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0435

AC:

462

AN:

10612

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0631

AC:

4294

AN:

68006

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

304

608

912

1216

1520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0548

Hom.:

186

Bravo

AF:

0.0431

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

Kabuki syndrome

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.59

(source)

DANN

Benign

0.58

PhyloP100

-3.9

PromoterAI

0.18

Neutral

(source)

Mutation Taster

=99/1

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