7-105110867-A-G

Variant names:

• chr7-105110867-A-G
• NM_182931.3:c.4067A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182931.3(KMT2E):​c.4067A>G​(p.Lys1356Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,454,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KMT2E NM_182931.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.34

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]

SRPK2 (HGNC:11306): (SRSF protein kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including nucleic acid metabolic process; peptidyl-serine phosphorylation; and regulation of viral genome replication. Located in chromatin; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2E	NM_182931.3	c.4067A>G	p.Lys1356Arg	missense_variant, splice_region_variant	Exon 26 of 27	ENST00000311117.8	NP_891847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2E	ENST00000311117.8	c.4067A>G	p.Lys1356Arg	missense_variant, splice_region_variant	Exon 26 of 27	1	NM_182931.3	ENSP00000312379.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454662 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724258

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.40	T;T
Polyphen		0.99	D;D
Vest4		0.43
MutPred		0.28		Loss of methylation at K1356 (P = 0.0028);Loss of methylation at K1356 (P = 0.0028);
MVP		0.73
MPC		0.090
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-104751314;