rs200601717

chr12-49037694-G-Achr12-49037694-G-Cchr12-49037694-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.9662C>T(p.Thr3221Ile) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3221N) 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: 3.18

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=0.14736989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.9662C>T	p.Thr3221Ile	missense_variant	35/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.9662C>T	p.Thr3221Ile	missense_variant	35/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Benign	0.78
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D
Polyphen		0.090	B
Vest4		0.20
MutPred		0.21		Loss of phosphorylation at T3221 (P = 0.0189);
MVP		0.27
MPC		0.33
ClinPred		0.24	T
GERP RS		2.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.7
Varity_R		0.072
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: chr12-49431477;