12-49032905-G-C

Position:

• chr12-49032905-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003482.4(KMT2D):​c.11800C>G​(p.Gln3934Glu) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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 where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.3619503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.11800C>G	p.Gln3934Glu	missense_variant	40/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.11800C>G	p.Gln3934Glu	missense_variant	40/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.28
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Polyphen		0.64	P
Vest4		0.55
MutPred		0.34		Loss of MoRF binding (P = 0.2918);
MVP		0.23
MPC		0.16
ClinPred		0.24	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.23

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: chr12-49426688;