chr12-49038582-G-A

Position:

chr12-49038582-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_003482.4(KMT2D):c.8774C>T(p.Ala2925Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,538 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: 1.82

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 -8 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=0.0050002933).

BP6

Variant 12-49038582-G-A is Benign according to our data. Variant chr12-49038582-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94260.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1, Benign=4}. Variant chr12-49038582-G-A is described in Lovd as [Likely_benign]. Variant chr12-49038582-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.8774C>T	p.Ala2925Val	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.8774C>T	p.Ala2925Val	missense_variant	35/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

329

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00166

AC:

410

AN:

247666

Hom.:

AF XY:

0.00164

AC XY:

221

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00295

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00237

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00213

AC:

3107

AN:

1460258

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1489

AN XY:

726222

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00146

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00228

Gnomad4 NFE exome

AF:

0.00240

Gnomad4 OTH exome

AF:

0.00186

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152280

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00250

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.00235

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00187

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00171

AC:

207

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2017	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KMT2D: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2019	This variant is associated with the following publications: (PMID: 30459467, 30107592, 28389907, 29627316, 28440294) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Kabuki syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Kabuki syndrome

Benign:1

Likely 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

0.094

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.044

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Uncertain

0.0040

Polyphen

0.0040

Vest4

0.087

MVP

0.31

MPC

0.16

ClinPred

0.011

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.088

gMVP

0.18

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