7-105110773-C-T

Variant names:

• chr7-105110773-C-T
• rs187060721
• NM_182931.3:c.3973C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182931.3(KMT2E):​c.3973C>T​(p.Pro1325Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,612,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: KMT2E NM_182931.3 missense, splice_region
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.76
• Publications: 3 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010281444).
• BP6: Variant 7-105110773-C-T is Benign according to our data. Variant chr7-105110773-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2074720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000467 (71/152124) while in subpopulation AMR AF = 0.00151 (23/15270). AF 95% confidence interval is 0.00103. There are 1 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 71 AD gene.

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.3973C>T	p.Pro1325Ser	missense splice_region	Exon 26 of 27	NP_891847.1	Q8IZD2-1
	KMT2E	NM_018682.4		c.3973C>T	p.Pro1325Ser	missense splice_region	Exon 25 of 26	NP_061152.3
	KMT2E	NM_001410908.1		c.3847C>T	p.Pro1283Ser	missense splice_region	Exon 24 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.3973C>T	p.Pro1325Ser	missense splice_region	Exon 26 of 27	ENSP00000312379.3	Q8IZD2-1
	KMT2E	ENST00000473063.2	TSL:1	c.3847C>T	p.Pro1283Ser	missense splice_region	Exon 24 of 25	ENSP00000417156.2	Q8IZD2-7
	KMT2E	ENST00000257745.9	TSL:1	n.*2612C>T		splice_region non_coding_transcript_exon	Exon 26 of 27	ENSP00000257745.5	A0A8J9FJW2

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152006 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.000647

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251306 AF XY: 0.000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1460506 Hom.: 0 Cov.: 30 AF XY: 0.000389 AC XY: 283 AN XY: 726642

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.000693 AC: 31 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000508 AC: 564 AN: 1110778

Other (OTH) AF: 0.000331 AC: 20 AN: 60356

GnomAD4 genome AF: 0.000467 AC: 71 AN: 152124 Hom.: 1 Cov.: 31 AF XY: 0.000471 AC XY: 35 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41500

American (AMR) AF: 0.00151 AC: 23 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 67988

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	KMT2E-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.16
Sift	Benign	0.035	D
Sift4G	Benign	0.50	T
Polyphen		0.041	B
Vest4		0.37
MVP		0.34
MPC		0.065
ClinPred		0.055	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.24
Mutation Taster		=83/17	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: rs187060721; hg19: chr7-104751220;