rs587783702

chr12-49022151-C-Achr12-49022151-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_003482.4(KMT2D):c.16413G>T(p.Arg5471Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5471K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense, splice_region
• Scores: Splicing: ADA: 0.9859
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.34

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain SET (size 116) in uniprot entity KMT2D_HUMAN there are 38 pathogenic changes around while only 5 benign (88%) 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 chr12-49022280-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KMT2D
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-49022151-C-A is Pathogenic according to our data. Variant chr12-49022151-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158743.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.16413G>T	p.Arg5471Ser	missense_variant, splice_region_variant	54/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.16413G>T	p.Arg5471Ser	missense_variant, splice_region_variant	54/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 10, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	33
Dann	Benign	0.93
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.89		Gain of glycosylation at R5471 (P = 0.029);.;
MVP		0.99
MPC		1.7
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587783702; hg19: chr12-49415934;