Genetic Variant NM_003482.4:c.7479G>T (chr12-49040291-C-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003482.4(KMT2D):c.7479G>T(p.Gly2493Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,598,928 control chromosomes in the GnomAD database, including 143,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14147 hom., cov: 32)

Exomes 𝑓: 0.42 ( 129384 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0400

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 12-49040291-C-A is Benign according to our data. Variant chr12-49040291-C-A is described in ClinVar as [Benign]. Clinvar id is 94248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49040291-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.7479G>T	p.Gly2493Gly	synonymous_variant	Exon 32 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.7479G>T	p.Gly2493Gly	synonymous_variant	Exon 32 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65077

AN:

151750

Hom.:

14123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.407

GnomAD3 exomes

AF:

0.411

AC:

96468

AN:

234900

Hom.:

20150

AF XY:

0.416

AC XY:

53322

AN XY:

128132

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.443

Gnomad SAS exome

AF:

0.461

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.412

GnomAD4 exome

AF:

0.421

AC:

608568

AN:

1447060

Hom.:

129384

Cov.:

AF XY:

0.421

AC XY:

302770

AN XY:

718434

show subpopulations

Gnomad4 AFR exome

AF:

0.475

Gnomad4 AMR exome

AF:

0.300

Gnomad4 ASJ exome

AF:

0.295

Gnomad4 EAS exome

AF:

0.401

Gnomad4 SAS exome

AF:

0.450

Gnomad4 FIN exome

AF:

0.435

Gnomad4 NFE exome

AF:

0.425

Gnomad4 OTH exome

AF:

0.420

GnomAD4 genome

AF:

0.429

AC:

65151

AN:

151868

Hom.:

14147

Cov.:

AF XY:

0.427

AC XY:

31653

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.470

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.281

Gnomad4 EAS

AF:

0.432

Gnomad4 SAS

AF:

0.467

Gnomad4 FIN

AF:

0.428

Gnomad4 NFE

AF:

0.425

Gnomad4 OTH

AF:

0.406

Alfa

AF:

0.369

Hom.:

2857

Bravo

AF:

0.420

Asia WGS

AF:

0.450

AC:

1563

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome 1

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

DANN

Benign

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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