rs186696516

Positions:

• chr12-49033564-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_003482.4(KMT2D):​c.11141G>A​(p.Arg3714Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,488 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts 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. R3714S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 2.41

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.008363575).
• BP6: Variant 12-49033564-C-T is Benign according to our data. Variant chr12-49033564-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.11141G>A	p.Arg3714Lys	missense_variant	40/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.11141G>A	p.Arg3714Lys	missense_variant	40/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152002 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00562

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00313 AC: 777 AN: 248550 Hom.: 8 AF XY: 0.00296 AC XY: 400 AN XY: 134990

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00634

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00121 AC: 1770 AN: 1461368 Hom.: 28 Cov.: 46 AF XY: 0.00117 AC XY: 853 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00312

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152120 Hom.: 9 Cov.: 33 AF XY: 0.00284 AC XY: 211 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00563

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00257 AC: 311

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -

Kabuki syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

KMT2D: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.82	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.43
MVP		0.63
MPC		0.53
ClinPred		0.056	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.60

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: rs186696516; hg19: chr12-49427347; COSMIC: COSV56417686; COSMIC: COSV56417686;