12-49037164-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):c.10192A>G(p.Met3398Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,592,154 control chromosomes in the GnomAD database, including 101 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3398L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (93 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.35

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=0.006613195).
• BP6: Variant 12-49037164-T-C is Benign according to our data. Variant chr12-49037164-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49037164-T-C is described in Lovd as [Benign]. Variant chr12-49037164-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (1235/152352) while in subpopulation NFE AF= 0.0124 (844/68034). AF 95% confidence interval is 0.0117. There are 8 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.10192A>G	p.Met3398Val	missense_variant	35/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.10192A>G	p.Met3398Val	missense_variant	35/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152234 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00879 AC: 2117 AN: 240902 Hom.: 18 AF XY: 0.00897 AC XY: 1172 AN XY: 130610

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.000727

Gnomad SAS exome AF: 0.00241

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00907

GnomAD4 exome AF: 0.0108 AC: 15489 AN: 1439802 Hom.: 93 Cov.: 32 AF XY: 0.0107 AC XY: 7610 AN XY: 712170

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00535

Gnomad4 EAS exome AF: 0.000459

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.00960

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152352 Hom.: 8 Cov.: 32 AF XY: 0.00801 AC XY: 597 AN XY: 74494

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00970 Hom.: 5

Bravo AF: 0.00709

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00120 AC: 5

ESP6500EA AF: 0.0119 AC: 101

ExAC AF: 0.00941 AC: 1139

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 16, 2015	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	This variant is associated with the following publications: (PMID: 30459467, 30107592, 24728327, 24633898) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KMT2D: BP4, BS1, BS2 -

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)	Apr 17, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2013	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	12
Dann	Benign	0.88
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.022
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Polyphen		0.0	B
Vest4		0.70
MVP		0.43
MPC		0.15
ClinPred		0.013	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75937132; hg19: chr12-49430947; COSMIC: COSV56422093; COSMIC: COSV56422093;