rs398123756

chr12-49040735-C-Achr12-49040735-C-Gchr12-49040735-C-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.7035G>T(p.Leu2345Phe) 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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L2345L) 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: 0.326

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=0.18128896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.7035G>T	p.Leu2345Phe	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.7035G>T	p.Leu2345Phe	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.0066
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.89	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Polyphen		0.95	P
Vest4		0.26
MutPred		0.16		Gain of glycosylation at S2342 (P = 0.0861);
MVP		0.33
MPC		0.60
ClinPred		0.35	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.048

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: chr12-49434518;