12-49033564-C-T

Position:

chr12-49033564-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.11141G>A(p.Arg3714Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,488 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3714S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 28 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 2.41

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=0.008363575).

BP6

Variant 12-49033564-C-T is Benign according to our data. Variant chr12-49033564-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.11141G>A	p.Arg3714Lys	missense_variant	40/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.11141G>A	p.Arg3714Lys	missense_variant	40/55	5	NM_003482.4	A2	O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00562

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00313

AC:

777

AN:

248550

Hom.:

AF XY:

0.00296

AC XY:

400

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00634

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.000826

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00121

AC:

1770

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

853

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00312

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0264

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.00204

AC:

310

AN:

152120

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00563

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00257

AC:

311

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -

Kabuki syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

KMT2D: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.041

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0084

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.82

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.97

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

Polyphen

0.99

Vest4

0.43

MVP

0.63

MPC

0.53

ClinPred

0.056

GERP RS

5.1

Varity_R

0.24

gMVP

0.60

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