12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_003482.4(KMT2D):c.11222_11223insGCA(p.Gln3744dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0014 in 1,611,336 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: KMT2D NM_003482.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.57

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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003482.4
• BP6: Variant 12-49033482-T-TTGC is Benign according to our data. Variant chr12-49033482-T-TTGC is described in ClinVar as [Likely_benign]. Clinvar id is 94150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 261 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.11222_11223insGCA	p.Gln3744dup	inframe_insertion	40/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.11222_11223insGCA	p.Gln3744dup	inframe_insertion	40/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 151764 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00164 AC: 384 AN: 233912 Hom.: 2 AF XY: 0.00163 AC XY: 207 AN XY: 127272

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.000276

Gnomad ASJ exome AF: 0.00604

Gnomad EAS exome AF: 0.00213

Gnomad SAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.00335

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00136 AC: 1991 AN: 1459450 Hom.: 5 Cov.: 47 AF XY: 0.00144 AC XY: 1043 AN XY: 726016

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.00621

Gnomad4 EAS exome AF: 0.000807

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00394

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00172 AC: 261 AN: 151886 Hom.: 0 Cov.: 33 AF XY: 0.00170 AC XY: 126 AN XY: 74262

Gnomad4 AFR AF: 0.000676

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.00195

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.00190

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	This variant is associated with the following publications: (PMID: 30107592, 27302555, 23757202) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KMT2D: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2019	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2012	- -

Kabuki syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123707; hg19: chr12-49427265;