12-49049851-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003482.4(KMT2D):c.3737C>G(p.Thr1246Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T1246M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KMT2D

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.3737C>G	p.Thr1246Arg	missense_variant	12/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.3737C>G	p.Thr1246Arg	missense_variant	12/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.3737C>G	p.Thr1246Arg	missense_variant	12/56			P4
KMT2D	ENST00000685166.1	c.3737C>G	p.Thr1246Arg	missense_variant	11/54			A2
KMT2D	ENST00000692637.1	c.3737C>G	p.Thr1246Arg	missense_variant	11/54			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.88	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.13		Gain of methylation at T1246 (P = 0.0378);
MVP		0.51
MPC		0.78
ClinPred		0.59	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49443634;