rs398123724

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_003482.4(KMT2D):c.15142C>T(p.Arg5048Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5048H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 4.20

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a zinc_finger_region C2HC pre-PHD-type 2 (size 40) in uniprot entity KMT2D_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003482.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-49026823-C-T is described in Lovd as [Pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 12-49026824-G-A is Pathogenic according to our data. Variant chr12-49026824-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 94180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49026824-G-A is described in Lovd as [Pathogenic]. Variant chr12-49026824-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.15142C>T	p.Arg5048Cys	missense_variant	49/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.15142C>T	p.Arg5048Cys	missense_variant	49/55	5	NM_003482.4	ENSP00000301067	A2	O14686-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kabuki syndrome 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 21671394, 27302555, 25972376] -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Apr 17, 2014	- -
Likely pathogenic, no assertion criteria provided	research	Shaikh Laboratory, University of Colorado	Feb 04, 2015	- -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patients with Kabuki syndrome in published literature (Hannibal et al., 2011; Bogershausen et al., 2016); This variant is associated with the following publications: (PMID: 27302555, 30459467, 23913813, 19625956, 23320472, 22126750, 30176882, 29682684, 25972376, 28404210, 21671394, 29089047) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2020	- -

Kabuki syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2018

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). This variant has been reported in multiple individuals affected with Kabuki syndrome including at least 5 individuals in whom the variant have been confirmed to be de novo (PMID: 21671394, 27302555, 25972376, 23913813). It has also been found in a mother and daughter with Kabuki syndrome (PMID: 19625956, 22126750). ClinVar contains an entry for this variant (Variation ID: 94180). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 5048 of the KMT2D protein (p.Arg5048Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2020

The c.15142C>T (p.R5048C) alteration is located in exon 48 (coding exon 48) of the KMT2D gene. This alteration results from a C to T substitution at nucleotide position 15142, causing the arginine (R) at amino acid position 5048 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the KMT2D c.15142C>T alteration was not observed, with coverage at this position. This mutation was identified in multiple individuals with Kabuki syndrome (Hannibal, 2011; Banka, 2012; Makrythanasis, 2013; Van Laarhoven, 2015), including one de novo case (Miyake, 2013). The p.R5048C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.49

Loss of disorder (P = 0.0354);

MVP

0.92

MPC

1.3

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.93

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