12-49054680-C-T

Position:

chr12-49054680-C-T

Variant summary

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

The NM_003482.4(KMT2D):c.248G>A(p.Arg83Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,612,688 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 73 hom., cov: 32)

Exomes 𝑓: 0.027 ( 660 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.648

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=0.00251621).

BP6

Variant 12-49054680-C-T is Benign according to our data. Variant chr12-49054680-C-T is described in ClinVar as [Benign]. Clinvar id is 94203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49054680-C-T is described in Lovd as [Benign]. Variant chr12-49054680-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0242 (3680/152244) while in subpopulation NFE AF= 0.0344 (2338/68006). AF 95% confidence interval is 0.0332. There are 73 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3680 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.248G>A	p.Arg83Gln	missense_variant	4/55	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.248G>A	p.Arg83Gln	missense_variant	4/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3682

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0542

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0259

AC:

6318

AN:

243934

Hom.:

AF XY:

0.0264

AC XY:

3501

AN XY:

132690

show subpopulations

Gnomad AFR exome

AF:

0.00421

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0248

Gnomad FIN exome

AF:

0.0479

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0275

AC:

40154

AN:

1460444

Hom.:

660

Cov.:

AF XY:

0.0275

AC XY:

19942

AN XY:

726442

show subpopulations

Gnomad4 AFR exome

AF:

0.00389

Gnomad4 AMR exome

AF:

0.0169

Gnomad4 ASJ exome

AF:

0.0221

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.0465

Gnomad4 NFE exome

AF:

0.0291

Gnomad4 OTH exome

AF:

0.0258

GnomAD4 genome

AF:

0.0242

AC:

3680

AN:

152244

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00445

Gnomad4 AMR

AF:

0.0209

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0215

Gnomad4 FIN

AF:

0.0542

Gnomad4 NFE

AF:

0.0344

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.0300

Hom.:

122

Bravo

AF:

0.0196

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0288

AC:

111

ESP6500AA

AF:

0.00554

AC:

ESP6500EA

AF:

0.0309

AC:

256

ExAC

AF:

0.0258

AC:

3119

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 31, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.70

N;N

REVEL

Benign

0.26

Sift

Benign

0.38

T;T

Polyphen

0.0040

B;.

Vest4

0.074

MPC

0.21

ClinPred

0.0043

GERP RS

3.3

Varity_R

0.039

gMVP

0.39

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