rs1949185080

Variant names:

• chr11-118436605-G-A
• rs1949185080
• NM_001197104.2:c.93G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001197104.2(KMT2A):​c.93G>A​(p.Pro31Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,163,526 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: KMT2A NM_001197104.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.80
• Publications: 0 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-118436605-G-A is Benign according to our data. Variant chr11-118436605-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2026903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	NM_001197104.2	MANE Select	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 36	NP_005924.2	Q03164-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.93G>A	p.Pro31Pro	synonymous	Exon 1 of 36	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-798-32170G>A		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.86e-7 AC: 1 AN: 1013892 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 477906

African (AFR) AF: 0.00 AC: 0 AN: 20490

American (AMR) AF: 0.00 AC: 0 AN: 6274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11406

East Asian (EAS) AF: 0.0000482 AC: 1 AN: 20730

South Asian (SAS) AF: 0.00 AC: 0 AN: 18804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 872256

Other (OTH) AF: 0.00 AC: 0 AN: 38620

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149634 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73058

African (AFR) AF: 0.0000243 AC: 1 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67134

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		1.8
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs1949185080; hg19: chr11-118307320;