12-49049851-G-T

Variant summary

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

The NM_003482.4(KMT2D):c.3737C>A(p.Thr1246Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• 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>A	p.Thr1246Lys	missense_variant	12/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.3737C>A	p.Thr1246Lys	missense_variant	12/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.3737C>A	p.Thr1246Lys	missense_variant	12/56			P4
KMT2D	ENST00000685166.1	c.3737C>A	p.Thr1246Lys	missense_variant	11/54			A2
KMT2D	ENST00000692637.1	c.3737C>A	p.Thr1246Lys	missense_variant	11/54			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249018 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461614 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.83	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.15		Gain of ubiquitination at T1246 (P = 0.0014);
MVP		0.45
MPC		0.79
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs112921115; hg19: chr12-49443634;