11-118436597-G-A

Variant names:

• chr11-118436597-G-A
• rs1161519468
• NM_001197104.2:c.85G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001197104.2(KMT2A):​c.85G>A​(p.Gly29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000982 in 1,018,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G29C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 1 publications found

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]

KMT2A Gene-Disease associations (from GenCC):

• Wiedemann-Steiner syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19467047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.85G>A	p.Gly29Ser	missense_variant	Exon 1 of 36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.85G>A	p.Gly29Ser	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.-798-32178G>A		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.82e-7 AC: 1 AN: 1018404 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 480176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20646

American (AMR) AF: 0.00 AC: 0 AN: 6436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11620

East Asian (EAS) AF: 0.00 AC: 0 AN: 21332

South Asian (SAS) AF: 0.00 AC: 0 AN: 18848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2668

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 874314

Other (OTH) AF: 0.00 AC: 0 AN: 38972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.0	N;N;.;N
PhyloP100		2.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.50	N;N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.015	D;D;D;.
Sift4G	Uncertain	0.033	D;T;D;.
Polyphen		0.84, 0.95	.;P;P;.
Vest4		0.21
MutPred		0.14		Gain of phosphorylation at G29 (P = 0.0177);Gain of phosphorylation at G29 (P = 0.0177);Gain of phosphorylation at G29 (P = 0.0177);Gain of phosphorylation at G29 (P = 0.0177);
MVP		0.64
MPC		0.79
ClinPred		0.25	T
GERP RS		1.8
PromoterAI		-0.088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.26
gMVP		0.34
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1161519468; hg19: chr11-118307312;