rs150073007

Positions:

• chr7-152247986-G-GT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_170606.3(KMT2C):​c.2447_2448insA​(p.Tyr816Ter) variant causes a stop gained, frameshift change. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.49 (0 hom., cov: 0)
  • Exomes 𝑓: 0.49 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2C NM_170606.3 stop_gained, frameshift
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.77

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-152247986-G-GT is Benign according to our data. Variant chr7-152247986-G-GT is described in ClinVar as [Benign]. Clinvar id is 403020.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.2447_2448insA	p.Tyr816Ter	stop_gained, frameshift_variant	14/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.2447_2448insA	p.Tyr816Ter	stop_gained, frameshift_variant	14/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 72119 AN: 145804 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.492 AC: 635498 AN: 1292742 Hom.: 0 Cov.: 75 AF XY: 0.492 AC XY: 317601 AN XY: 645684

Gnomad4 AFR exome AF: 0.496

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.489

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.495 AC: 72179 AN: 145924 Hom.: 0 Cov.: 0 AF XY: 0.495 AC XY: 35339 AN XY: 71454

Gnomad4 AFR AF: 0.497

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.500

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.493

Gnomad4 OTH AF: 0.493

Alfa AF: 0.488 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

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: rs150073007; hg19: chr7-151945071;