12-49026430-C-A

Position:

• chr12-49026430-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_003482.4(KMT2D):​c.15536G>T​(p.Arg5179Leu) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5179C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain FYR N-terminal (size 60) in uniprot entity KMT2D_HUMAN there are 19 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 chr12-49026431-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 12-49026430-C-A is Pathogenic according to our data. Variant chr12-49026430-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981669.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-49026430-C-A is described in Lovd as [Pathogenic]. Variant chr12-49026430-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.15536G>T	p.Arg5179Leu	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	c.15536G>T	p.Arg5179Leu	missense_variant	49/55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Autoinflammatory diseases unit, CHU de Montpellier

Oct 01, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.60		Loss of MoRF binding (P = 0.0202);
MVP		0.89
MPC		1.2
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.76
gMVP		0.94

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

Other links and lift over

dbSNP: rs267607237; hg19: chr12-49420213; COSMIC: COSV56447076; COSMIC: COSV56447076;