12-49021865-T-C

Position:

• chr12-49021865-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_003482.4(KMT2D):​c.16529A>G​(p.Tyr5510Cys) 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. Y5510D) has been classified as Likely pathogenic.

• 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: 7.93

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]

ENSG00000288710 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain SET (size 116) in uniprot entity KMT2D_HUMAN there are 26 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 chr12-49021866-A-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2D. . Gene score misZ 3.7288 (greater than the threshold 3.09). Trascript score misZ 4.6964 (greater than threshold 3.09). GenCC has associacion of gene with Kabuki syndrome, branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, Kabuki syndrome 1, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 12-49021865-T-C is Pathogenic according to our data. Variant chr12-49021865-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1701876.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	Protein	UniProt
KMT2D	NM_003482.4	c.16529A>G	p.Tyr5510Cys	missense_variant	55/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.16529A>G	p.Tyr5510Cys	missense_variant	55/55	5	NM_003482.4	ENSP00000301067.7
ENSG00000288710	ENST00000683988.1	n.500A>G		non_coding_transcript_exon_variant	5/16			ENSP00000506939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 5510 of the KMT2D protein (p.Tyr5510Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 25363768, 31785789, 34011629, 35982160). ClinVar contains an entry for this variant (Variation ID: 1701876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KMT2D protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr5510 amino acid residue in KMT2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24633898, 30107592). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.75		Loss of phosphorylation at Y5510 (P = 0.03);.;
MVP		0.93
MPC		1.9
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.90
gMVP		0.99

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: rs1383821738; hg19: chr12-49415648;