rs398123724

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5048H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 4.20

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
Kabuki syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Kabuki syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94180.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.15142C>T	p.Arg5048Cys	missense_variant	Exon 49 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.15142C>T	p.Arg5048Cys	missense_variant	Exon 49 of 55	5	NM_003482.4	ENSP00000301067.7		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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111324

Other (OTH)

AF:

0.00

AC:

AN:

60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kabuki syndrome 1

Pathogenic:4

Mar 07, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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] -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS4, PM2, PP3 -

Apr 17, 2014

Autoinflammatory diseases unit, CHU de Montpellier

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2015

Shaikh Laboratory, University of Colorado

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:2Uncertain:1

Mar 13, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jan 21, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Pathogenic:1

Jan 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 15, 2020

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.2

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

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over