rs891241557

Variant names:

• chr7-105040965-A-T
• rs891241557
• NM_182931.3:c.13A>T

Variant summary

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

The NM_182931.3(KMT2E):​c.13A>T​(p.Ile5Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I5N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KMT2E NM_182931.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.31
• Publications: 0 publications found

Genes affected

KMT2E (HGNC:18541): (lysine methyltransferase 2E (inactive)) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a central SET domain. Overexpression of the protein inhibits cell cycle progression. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

KMT2E Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• O'Donnell-Luria-Rodan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288914 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182931.3. 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
	KMT2E	NM_182931.3	MANE Select	c.13A>T	p.Ile5Phe	missense	Exon 3 of 27	NP_891847.1	Q8IZD2-1
	KMT2E	NM_018682.4		c.13A>T	p.Ile5Phe	missense	Exon 2 of 26	NP_061152.3
	KMT2E	NM_001410908.1		c.13A>T	p.Ile5Phe	missense	Exon 2 of 25	NP_001397837.1	Q8IZD2-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2E	ENST00000311117.8	TSL:1 MANE Select	c.13A>T	p.Ile5Phe	missense	Exon 3 of 27	ENSP00000312379.3	Q8IZD2-1
	KMT2E	ENST00000473063.2	TSL:1	c.13A>T	p.Ile5Phe	missense	Exon 2 of 25	ENSP00000417156.2	Q8IZD2-7
	KMT2E	ENST00000476671.5	TSL:1	c.13A>T	p.Ile5Phe	missense	Exon 3 of 15	ENSP00000417888.1	Q8IZD2-3

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150624 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000490

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: 6.85e-7 AC: 1 AN: 1460416 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726570

African (AFR) AF: 0.0000299 AC: 1 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111232

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150624 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73408

African (AFR) AF: 0.0000490 AC: 2 AN: 40804

American (AMR) AF: 0.00 AC: 0 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	O'Donnell-Luria-Rodan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.44	B
Vest4		0.76
MVP		0.87
MPC		0.87
ClinPred		0.89	D
GERP RS		5.5
PromoterAI		0.015	Neutral
Varity_R		0.22
gMVP		0.61
Mutation Taster		=70/30	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: rs891241557; hg19: chr7-104681412;