rs9332745

Positions:

• chr11-118436601-C-G
• chr11-118436601-C-T

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.89C>G​(p.Ala30Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,166,772 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.025 (368 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.13

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]

ENSG00000285827 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2A. . Gene score misZ: 6.2276 (greater than the threshold 3.09). Trascript score misZ: 8.7715 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 124 curated benign missense variants. GenCC has associacion of the gene with Wiedemann-Steiner syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043572187).
• BP6: Variant 11-118436601-C-G is Benign according to our data. Variant chr11-118436601-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118436601-C-G is described in Lovd as [Benign]. Variant chr11-118436601-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2276/149684) while in subpopulation NFE AF= 0.0243 (1635/67156). AF 95% confidence interval is 0.0234. There are 29 homozygotes in gnomad4. There are 1066 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.89C>G	p.Ala30Gly	missense_variant	1/36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.89C>G	p.Ala30Gly	missense_variant	1/36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.-798-32174C>G		intron_variant				ENSP00000498126.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2278 AN: 149574 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00436

Gnomad AMI AF: 0.0221

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0146

GnomAD3 exomes AF: 0.0310 AC: 123 AN: 3974 Hom.: 6 AF XY: 0.0307 AC XY: 64 AN XY: 2084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0250 AC: 25425 AN: 1017088 Hom.: 368 Cov.: 23 AF XY: 0.0249 AC XY: 11951 AN XY: 479602

Gnomad4 AFR exome AF: 0.00330

Gnomad4 AMR exome AF: 0.00942

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00509

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.0272

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0152 AC: 2276 AN: 149684 Hom.: 29 Cov.: 32 AF XY: 0.0146 AC XY: 1066 AN XY: 73118

Gnomad4 AFR AF: 0.00435

Gnomad4 AMR AF: 0.00736

Gnomad4 ASJ AF: 0.00232

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00458

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0243

Gnomad4 OTH AF: 0.0139

Alfa AF: 0.0181 Hom.: 9

Bravo AF: 0.0133

ExAC AF: 0.00824 AC: 39

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	This variant is associated with the following publications: (PMID: 28386644) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.13	.;T;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.34	N;N;.;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.19	N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.076	T;T;D;.
Sift4G	Benign	0.17	T;T;T;.
Polyphen		0.95, 0.64	.;P;P;.
Vest4		0.17
MPC		0.80
ClinPred		0.18	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.17
gMVP		0.27

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: rs9332745; hg19: chr11-118307316;