rs75226229

chr12-49051245-G-Achr12-49051245-G-Cchr12-49051245-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003482.4(KMT2D):c.2438C>T(p.Pro813Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,534,894 control chromosomes in the GnomAD database, including 2,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P813R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (202 hom., cov: 28)
  • Exomes 𝑓: 0.051 (2163 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.479

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015470386).
• BP6: Variant 12-49051245-G-A is Benign according to our data. Variant chr12-49051245-G-A is described in ClinVar as [Benign]. Clinvar id is 94202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49051245-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.2438C>T	p.Pro813Leu	missense_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.2438C>T	p.Pro813Leu	missense_variant	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.2438C>T	p.Pro813Leu	missense_variant	11/56			P4
KMT2D	ENST00000685166.1	c.2438C>T	p.Pro813Leu	missense_variant	10/54			A2
KMT2D	ENST00000692637.1	c.2438C>T	p.Pro813Leu	missense_variant	10/54			A2

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6300 AN: 151202 Hom.: 202 Cov.: 28

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0665

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0240

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0372

GnomAD3 exomes AF: 0.0420 AC: 7835 AN: 186726 Hom.: 264 AF XY: 0.0426 AC XY: 4263 AN XY: 100022

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.000125

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0511 AC: 70729 AN: 1383574 Hom.: 2163 Cov.: 34 AF XY: 0.0503 AC XY: 34266 AN XY: 681452

Gnomad4 AFR exome AF: 0.00688

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0942

Gnomad4 NFE exome AF: 0.0569

Gnomad4 OTH exome AF: 0.0441

GnomAD4 genome AF: 0.0416 AC: 6299 AN: 151320 Hom.: 202 Cov.: 28 AF XY: 0.0426 AC XY: 3149 AN XY: 73916

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.0345

Gnomad4 ASJ AF: 0.0240

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.0100

Gnomad4 FIN AF: 0.0981

Gnomad4 NFE AF: 0.0596

Gnomad4 OTH AF: 0.0368

Alfa AF: 0.0482 Hom.: 88

Bravo AF: 0.0344

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0592 AC: 228

ESP6500AA AF: 0.0112 AC: 45

ESP6500EA AF: 0.0515 AC: 424

ExAC AF: 0.0389 AC: 4672

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.94
Dann	Benign	0.37
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.023
Sift	Benign	0.055	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.19
ClinPred		0.00026	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.12

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: rs75226229; hg19: chr12-49445028; COSMIC: COSV56410262; COSMIC: COSV56410262;