chr12-49051245-G-A

Position:

chr12-49051245-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_003482.4(KMT2D):c.2438C>T(p.Pro813Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,534,894 control chromosomes in the GnomAD database, including 2,365 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P813R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.042 ( 202 hom., cov: 28)

Exomes 𝑓: 0.051 ( 2163 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.479

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=0.0015470386).

BP6

Variant 12-49051245-G-A is Benign according to our data. Variant chr12-49051245-G-A is described in ClinVar as [Benign]. Clinvar id is 94202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49051245-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.2438C>T	p.Pro813Leu	missense_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.2438C>T	p.Pro813Leu	missense_variant	11/55	5	NM_003482.4	A2	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.2438C>T	p.Pro813Leu	missense_variant	11/56			P4
KMT2D	ENST00000685166.1 linkuse as main transcript	c.2438C>T	p.Pro813Leu	missense_variant	10/54			A2	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.2438C>T	p.Pro813Leu	missense_variant	10/54			A2

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6300

AN:

151202

Hom.:

202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.0665

Gnomad AMR

AF:

0.0345

Gnomad ASJ

AF:

0.0240

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0981

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0596

Gnomad OTH

AF:

0.0372

GnomAD3 exomes

AF:

0.0420

AC:

7835

AN:

186726

Hom.:

264

AF XY:

0.0426

AC XY:

4263

AN XY:

100022

show subpopulations

Gnomad AFR exome

AF:

0.00769

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000125

Gnomad SAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.0952

Gnomad NFE exome

AF:

0.0577

Gnomad OTH exome

AF:

0.0450

GnomAD4 exome

AF:

0.0511

AC:

70729

AN:

1383574

Hom.:

2163

Cov.:

AF XY:

0.0503

AC XY:

34266

AN XY:

681452

show subpopulations

Gnomad4 AFR exome

AF:

0.00688

Gnomad4 AMR exome

AF:

0.0205

Gnomad4 ASJ exome

AF:

0.0231

Gnomad4 EAS exome

AF:

0.000153

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.0942

Gnomad4 NFE exome

AF:

0.0569

Gnomad4 OTH exome

AF:

0.0441

GnomAD4 genome

AF:

0.0416

AC:

6299

AN:

151320

Hom.:

202

Cov.:

AF XY:

0.0426

AC XY:

3149

AN XY:

73916

show subpopulations

Gnomad4 AFR

AF:

0.0107

Gnomad4 AMR

AF:

0.0345

Gnomad4 ASJ

AF:

0.0240

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.0100

Gnomad4 FIN

AF:

0.0981

Gnomad4 NFE

AF:

0.0596

Gnomad4 OTH

AF:

0.0368

Alfa

AF:

0.0482

Hom.:

Bravo

AF:

0.0344

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0592

AC:

228

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.0515

AC:

424

ExAC

AF:

0.0389

AC:

4672

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.94

DANN

Benign

0.37

DEOGEN2

Benign

0.043

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.40

REVEL

Benign

0.023

Sift

Benign

0.055

Polyphen

0.0

Vest4

0.048

MPC

0.19

ClinPred

0.00026

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.12

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

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