rs267607238

Variant names:

• chr12-49022301-G-A
• rs267607238
• NM_003482.4:c.16391C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49022301-G-A
• chr12-49022301-G-C
• chr12-49022301-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_003482.4(KMT2D):​c.16391C>T​(p.Thr5464Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T5464T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.01
• Publications: 9 publications found

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

ENSG00000288710 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003482.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-49022301-G-A is Pathogenic according to our data. Variant chr12-49022301-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7539.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.16391C>T	p.Thr5464Met	missense_variant	Exon 53 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.16391C>T	p.Thr5464Met	missense_variant	Exon 53 of 55	5	NM_003482.4	ENSP00000301067.7
ENSG00000288710	ENST00000683988.1	n.362C>T		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000506939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Sep 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Kabuki syndrome Pathogenic:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 5464 of the KMT2D protein (p.Thr5464Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Kabuki syndrome (PMID: 20711175, 25142838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7539). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KMT2D protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Mar 18, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.82		Loss of sheet (P = 0.0817);.;
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.93
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs267607238; hg19: chr12-49416084; COSMIC: COSV56409798; COSMIC: COSV56409798;