12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.11220_11222dupGCA(p.Gln3741dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0014 in 1,611,336 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 5 hom. )

Consequence

KMT2D
NM_003482.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.57

Publications

2 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003482.4

BP6

Variant 12-49033482-T-TTGC is Benign according to our data. Variant chr12-49033482-T-TTGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94150.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 = 0.00172 (261/151886) while in subpopulation NFE AF = 0.00209 (142/67870). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 261 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.11220_11222dupGCA	p.Gln3741dup	disruptive_inframe_insertion	Exon 40 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.11220_11222dupGCA	p.Gln3741dup	disruptive_inframe_insertion	Exon 40 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.11220_11222dupGCA	p.Gln3741dup	disruptive_inframe_insertion	Exon 40 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.11229_11231dupGCA	p.Gln3744dup	disruptive_inframe_insertion	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

261

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000678

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.00195

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00397

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00164

AC:

384

AN:

233912

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.000633

Gnomad AMR exome

AF:

0.000276

Gnomad ASJ exome

AF:

0.00604

Gnomad EAS exome

AF:

0.00213

Gnomad FIN exome

AF:

0.00335

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.00136

AC:

1991

AN:

1459450

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1043

AN XY:

726016

show subpopulations

African (AFR)

AF:

0.000927

AC:

AN:

33438

American (AMR)

AF:

0.000181

AC:

AN:

44234

Ashkenazi Jewish (ASJ)

AF:

0.00621

AC:

162

AN:

26100

East Asian (EAS)

AF:

0.000807

AC:

AN:

39638

South Asian (SAS)

AF:

0.000314

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00394

AC:

209

AN:

53024

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00130

AC:

1441

AN:

1110900

Other (OTH)

AF:

0.00123

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

119

237

356

474

593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.00172

AC:

261

AN:

151886

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

126

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.000676

AC:

AN:

41444

American (AMR)

AF:

0.000196

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

AN:

3464

East Asian (EAS)

AF:

0.00195

AC:

AN:

5124

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00397

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00209

AC:

142

AN:

67870

Other (OTH)

AF:

0.00190

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00103

Hom.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BS1, BS2

Oct 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 17, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30107592, 27302555, 23757202)

Oct 24, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Dec 19, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 08, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Kabuki syndrome

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Kabuki syndrome 1

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Mar 17, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.6

Mutation Taster

=60/40

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over