rs148585727

chr7-152162814-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2 PP3 BP4_Strong BP6_Very_Strong BS2

The NM_170606.3(KMT2C):c.10763C>T(p.Ser3588Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,614,094 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (13 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 9.59

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 Benign. Variant got -14 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2C
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.014497042).
• BP6: Variant 7-152162814-G-A is Benign according to our data. Variant chr7-152162814-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 428 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.10763C>T	p.Ser3588Leu	missense_variant	43/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.10763C>T	p.Ser3588Leu	missense_variant	43/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152110 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00268 AC: 673 AN: 250878 Hom.: 5 AF XY: 0.00265 AC XY: 359 AN XY: 135644

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00703

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00315 AC: 4602 AN: 1461866 Hom.: 13 Cov.: 33 AF XY: 0.00316 AC XY: 2297 AN XY: 727232

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152228 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74450

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00372 Hom.: 2

Bravo AF: 0.00228

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00253 AC: 307

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KMT2C: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

KMT2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.81
MVP		0.89
MPC		0.42
ClinPred		0.036	T
GERP RS		5.5
Varity_R		0.49
gMVP		0.45

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: rs148585727; hg19: chr7-151859899; COSMIC: COSV51415711; COSMIC: COSV51415711;