rs141727765

chr11-118502464-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001197104.2(KMT2A):c.6572G>A(p.Arg2191Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2191R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.60

Genes affected

KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.00980109).
• BP6: Variant 11-118502464-G-A is Benign according to our data. Variant chr11-118502464-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00108 (164/152090) while in subpopulation AMR AF= 0.00498 (76/15276). AF 95% confidence interval is 0.00407. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.6572G>A	p.Arg2191Gln	missense_variant	27/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.6572G>A	p.Arg2191Gln	missense_variant	27/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000964 AC: 240 AN: 248888 Hom.: 0 AF XY: 0.000965 AC XY: 130 AN XY: 134748

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00105 AC: 1533 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.00100 AC XY: 728 AN XY: 727204

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74330

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00498

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000840 AC: 102

EpiCase AF: 0.00120

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	KMT2A: BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 03, 2014

- -

Wiedemann-Steiner syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

KMT2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0098	T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.071	T;T;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.29	.;B;.
Vest4		0.14
MVP		0.67
MPC		0.68
ClinPred		0.014	T
GERP RS		5.8
Varity_R		0.049
gMVP		0.42

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: rs141727765; hg19: chr11-118373179;