chr12-49043616-T-G

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.5467+19A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,613,334 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 73 hom., cov: 32)

Exomes 𝑓: 0.028 ( 663 hom. )

Consequence

KMT2D
NM_003482.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.190

Publications

6 publications found

Variant links:

COSMIC-nc: COSV56432762

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 (BayesDel_noAF=-0.93).

BP6

Variant 12-49043616-T-G is Benign according to our data. Variant chr12-49043616-T-G is described in ClinVar as Benign. ClinVar VariationId is 94228.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 = 0.0242 (3692/152280) while in subpopulation NFE AF = 0.0345 (2347/68016). AF 95% confidence interval is 0.0333. There are 73 homozygotes in GnomAd4. There are 1821 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3692 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.5467+19A>C		intron_variant	Intron 24 of 54	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.5467+19A>C		intron_variant	Intron 24 of 54	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3692

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00442

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0543

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0345

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0259

AC:

6424

AN:

248410

AF XY:

0.0262

show subpopulations

Gnomad AFR exome

AF:

0.00395

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0483

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0275

AC:

40213

AN:

1461054

Hom.:

663

Cov.:

AF XY:

0.0275

AC XY:

19974

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.00388

AC:

130

AN:

33470

American (AMR)

AF:

0.0169

AC:

757

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

572

AN:

26090

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0251

AC:

2165

AN:

86238

European-Finnish (FIN)

AF:

0.0466

AC:

2483

AN:

53276

Middle Eastern (MID)

AF:

0.0245

AC:

141

AN:

5766

European-Non Finnish (NFE)

AF:

0.0292

AC:

32404

AN:

1111474

Other (OTH)

AF:

0.0258

AC:

1555

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2147

4294

6441

8588

10735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1136

2272

3408

4544

5680

<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:

0.0242

AC:

3692

AN:

152280

Hom.:

Cov.:

AF XY:

0.0245

AC XY:

1821

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41556

American (AMR)

AF:

0.0209

AC:

320

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0215

AC:

104

AN:

4830

European-Finnish (FIN)

AF:

0.0543

AC:

576

AN:

10600

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0345

AC:

2347

AN:

68016

Other (OTH)

AF:

0.0227

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0341

Hom.:

Bravo

AF:

0.0196

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 06, 2012

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

- -

Nov 20, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Kabuki syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

7.4

(source)

DANN

Benign

0.63

PhyloP100

0.19

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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