chr12-49037164-T-C

Position:

chr12-49037164-T-C

Variant summary

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

The NM_003482.4(KMT2D):c.10192A>G(p.Met3398Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,592,154 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 93 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.35

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:

KMT2D (HGNC:):

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=0.006613195).

BP6

Variant 12-49037164-T-C is Benign according to our data. Variant chr12-49037164-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49037164-T-C is described in Lovd as [Benign]. Variant chr12-49037164-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (1235/152352) while in subpopulation NFE AF= 0.0124 (844/68034). AF 95% confidence interval is 0.0117. There are 8 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.10192A>G	p.Met3398Val	missense_variant	35/55	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.10192A>G	p.Met3398Val	missense_variant	35/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1237

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00879

AC:

2117

AN:

240902

Hom.:

AF XY:

0.00897

AC XY:

1172

AN XY:

130610

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00502

Gnomad EAS exome

AF:

0.000727

Gnomad SAS exome

AF:

0.00241

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00907

GnomAD4 exome

AF:

0.0108

AC:

15489

AN:

1439802

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

7610

AN XY:

712170

show subpopulations

Gnomad4 AFR exome

AF:

0.00142

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.00535

Gnomad4 EAS exome

AF:

0.000459

Gnomad4 SAS exome

AF:

0.00229

Gnomad4 FIN exome

AF:

0.0154

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00960

GnomAD4 genome

AF:

0.00811

AC:

1235

AN:

152352

Hom.:

Cov.:

AF XY:

0.00801

AC XY:

597

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0191

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00970

Hom.:

Bravo

AF:

0.00709

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.0119

AC:

101

ExAC

AF:

0.00941

AC:

1139

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
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	GeneDx	Aug 16, 2018	This variant is associated with the following publications: (PMID: 30459467, 30107592, 24728327, 24633898) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KMT2D: BP4, BS1, BS2 -

Kabuki syndrome 1

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2014	- -
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	Jun 04, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.24

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.27

Sift

Uncertain

0.0020

Polyphen

0.0

Vest4

0.70

MVP

0.43

MPC

0.15

ClinPred

0.013

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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