12-49040121-G-T

Position:

• chr12-49040121-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_003482.4(KMT2D):​c.7649C>A​(p.Pro2550His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P2550T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.96

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP6: Variant 12-49040121-G-T is Benign according to our data. Variant chr12-49040121-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 566460.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.7649C>A	p.Pro2550His	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.7649C>A	p.Pro2550His	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.7649C>A (p.P2550H) alteration is located in exon 31 (coding exon 31) of the KMT2D gene. This alteration results from a C to A substitution at nucleotide position 7649, causing the proline (P) at amino acid position 2550 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

KMT2D-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2023

The KMT2D c.7649C>A variant is predicted to result in the amino acid substitution p.Pro2550His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Kabuki syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.84	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.39
Sift	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.16		Loss of catalytic residue at P2549 (P = 0.0116);
MVP		0.36
MPC		0.70
ClinPred		0.77	D
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.24
gMVP		0.14

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: rs368698254; hg19: chr12-49433904;