12-49031792-C-T

Position:

chr12-49031792-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_003482.4(KMT2D):c.12913G>A(p.Val4305Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,606,354 control chromosomes in the GnomAD database, including 9 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 8 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.227

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 -15 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=0.005800605).

BP6

Variant 12-49031792-C-T is Benign according to our data. Variant chr12-49031792-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49031792-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.12913G>A	p.Val4305Ile	missense_variant	40/55	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.12913G>A	p.Val4305Ile	missense_variant	40/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00136

AC:

328

AN:

240850

Hom.:

AF XY:

0.00139

AC XY:

182

AN XY:

130562

show subpopulations

Gnomad AFR exome

AF:

0.000458

Gnomad AMR exome

AF:

0.000590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000530

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00173

GnomAD4 exome

AF:

0.00340

AC:

4946

AN:

1454098

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

2272

AN XY:

722590

show subpopulations

Gnomad4 AFR exome

AF:

0.000570

Gnomad4 AMR exome

AF:

0.000724

Gnomad4 ASJ exome

AF:

0.0000786

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.000698

Gnomad4 NFE exome

AF:

0.00418

Gnomad4 OTH exome

AF:

0.00363

GnomAD4 genome

AF:

0.00189

AC:

288

AN:

152256

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00347

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000759

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00136

AC:

164

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KMT2D: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2019	This variant is associated with the following publications: (PMID: 24728327, 30459467) -
Likely 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)	Sep 14, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

Kabuki syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.038

Eigen

Benign

-0.14

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.28

REVEL

Benign

0.27

Sift

Uncertain

0.028

Polyphen

0.039

Vest4

0.17

MVP

0.20

MPC

0.12

ClinPred

0.0088

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.066

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