12-49049769-G-C

Variant names:

• chr12-49049769-G-C
• NM_003482.4:c.3819C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003482.4(KMT2D):​c.3819C>G​(p.Cys1273Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C1273C) 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: 1.72

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.3819C>G	p.Cys1273Trp	missense_variant	Exon 12 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.3819C>G	p.Cys1273Trp	missense_variant	Exon 12 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.3819C>G	p.Cys1273Trp	missense_variant	Exon 12 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.3819C>G	p.Cys1273Trp	missense_variant	Exon 11 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.3819C>G	p.Cys1273Trp	missense_variant	Exon 11 of 54			ENSP00000509666.1

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	0.35
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.042	T
Eigen	Benign	0.021
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.18		Gain of catalytic residue at L1271 (P = 0.0032);
MVP		0.24
MPC		0.85
ClinPred		0.58	D
GERP RS		3.4
Varity_R		0.35
gMVP		0.52

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: chr12-49443552;