12-49026736-A-G

Position:

• chr12-49026736-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_003482.4(KMT2D):​c.15230T>C​(p.Leu5077Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5077R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KMT2D
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 12-49026736-A-G is Pathogenic according to our data. Variant chr12-49026736-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197589.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.15230T>C	p.Leu5077Pro	missense_variant	49/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.15230T>C	p.Leu5077Pro	missense_variant	49/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2018

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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 observed to be de novo in an individual affected with a KMT2D-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 197589). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 5077 of the KMT2D protein (p.Leu5077Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.77		Loss of stability (P = 0.0322);
MVP		0.75
MPC		1.5
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs398123726; hg19: chr12-49420519;