12-49022633-C-T

Variant names:

• chr12-49022633-C-T
• rs398123734
• NM_003482.4:c.16295G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003482.4(KMT2D):​c.16295G>A​(p.Arg5432Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5432W) has been classified as Pathogenic.

• 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: 7.82
• Publications: 15 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: Pathogenic. The variant received 16 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49022634-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 633524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 12-49022633-C-T is Pathogenic according to our data. Variant chr12-49022633-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 94191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.16295G>A	p.Arg5432Gln	missense_variant	Exon 52 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.16295G>A	p.Arg5432Gln	missense_variant	Exon 52 of 55	5	NM_003482.4	ENSP00000301067.7
ENSG00000288710	ENST00000683988.1	n.266G>A		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000506939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KMT2D-related disorder Pathogenic:1

Mar 29, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KMT2D gene is constrained against variation (Z-score= 4.7 and pLI = 1), and missense variants are a common mechanism of disease (HGMD, ClinVar database; PMID: 21882399, 30107592). The c.16295G>A (p.Arg5432Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a recurrent variant that has been previously reported as a heterozygous change in patients with Kabuki syndrome (PMID: 36891680, 30107592, 31654559, 32803813, 32850830, 27302555). It has been reported in the de novo state (PMID: 37043208, 25896430, 31654559, 32170002) and as co-segregating with disease in a familial case (PMID: 22740433). A different amino acid change at the same residue (p.Arg5432Trp) has been previously reported in individuals with Kabuki syndrome (PMID: 33057194, 34374989, 22786791). The c.16295G>A (p.Arg5432Gln) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.16295G>A (p.Arg5432Gln) is classified as Pathogenic. -

not provided Uncertain:1

Jan 13, 2015

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	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.020	.;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.62		Loss of MoRF binding (P = 0.0707);.;
MVP		0.94
MPC		1.8
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.94
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs398123734; hg19: chr12-49416416; COSMIC: COSV56409187; COSMIC: COSV56409187;