12-49040100-G-A

Position:

chr12-49040100-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.7670C>T(p.Pro2557Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,613,868 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 91 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2D. . Gene score misZ 3.7288 (greater than the threshold 3.09). Trascript score misZ 4.6964 (greater than threshold 3.09). GenCC has associacion of gene with Kabuki syndrome, branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, Kabuki syndrome 1, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.005523622).

BP6

Variant 12-49040100-G-A is Benign according to our data. Variant chr12-49040100-G-A is described in ClinVar as [Benign]. Clinvar id is 94250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49040100-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1569/152320) while in subpopulation SAS AF= 0.017 (82/4834). AF 95% confidence interval is 0.0155. There are 14 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1569 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.7670C>T	p.Pro2557Leu	missense_variant	32/55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.7670C>T	p.Pro2557Leu	missense_variant	32/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1575

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.00614

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00824

AC:

2043

AN:

248030

Hom.:

AF XY:

0.00890

AC XY:

1200

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.0159

Gnomad AMR exome

AF:

0.00735

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0173

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.00733

AC:

10709

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

5632

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0158

Gnomad4 AMR exome

AF:

0.00769

Gnomad4 ASJ exome

AF:

0.0155

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0178

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.00619

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.0103

AC:

1569

AN:

152320

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

786

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.0169

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0170

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00615

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.00804

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.0140

AC:

ESP6500EA

AF:

0.00702

AC:

ExAC

AF:

0.00834

AC:

1008

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00851

EpiControl

AF:

0.00979

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Kabuki syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.23

Eigen

Benign

-0.16

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

Polyphen

0.0020

Vest4

0.38

MVP

0.18

MPC

0.65

ClinPred

0.021

GERP RS

4.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.12

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over