12-49052193-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003482.4(KMT2D):c.1490C>A(p.Pro497Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P497L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.10029492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.1490C>A	p.Pro497Gln	missense_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.1490C>A	p.Pro497Gln	missense_variant	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.1490C>A	p.Pro497Gln	missense_variant	11/56			P4
KMT2D	ENST00000685166.1	c.1490C>A	p.Pro497Gln	missense_variant	10/54			A2
KMT2D	ENST00000692637.1	c.1490C>A	p.Pro497Gln	missense_variant	10/54			A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Benign	0.70
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Polyphen		0.013	B
Vest4		0.32
MutPred		0.30		Loss of glycosylation at P497 (P = 0.0044);
MVP		0.16
MPC		0.17
ClinPred		0.13	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.092
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs371421459; hg19: chr12-49445976;