rs112620957

Positions:

• chr12-49050796-AG-A
• chr12-49050796-AG-AGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):​c.2798-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,594,394 control chromosomes in the GnomAD database, including 11 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: KMT2D NM_003482.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.15

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 -16 ACMG points.

• BP6: Variant 12-49050796-AG-A is Benign according to our data. Variant chr12-49050796-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 193865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49050796-AG-A is described in Lovd as [Likely_benign]. Variant chr12-49050796-AG-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00317 (482/152270) while in subpopulation AFR AF= 0.0107 (445/41526). AF 95% confidence interval is 0.00989. There are 4 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 482 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.2798-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.2798-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_003482.4	ENSP00000301067	A2
KMT2D	ENST00000683543.2	c.2798-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000506726	P4
KMT2D	ENST00000685166.1	c.2798-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000509386	A2
KMT2D	ENST00000692637.1	c.2798-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000509666	A2

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000811 AC: 193 AN: 237966 Hom.: 2 AF XY: 0.000609 AC XY: 79 AN XY: 129806

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000716

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: 0.0000185

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000342 AC: 493 AN: 1442124 Hom.: 7 Cov.: 35 AF XY: 0.000322 AC XY: 230 AN XY: 714818

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000802

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000327

Gnomad4 OTH exome AF: 0.000893

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74452

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Kabuki syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs112620957; hg19: chr12-49444579;