10-128101589-A-T

Position:

• chr10-128101589-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002417.5(MKI67):​c.9374T>A​(p.Met3125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.529

Genes affected

MKI67 (HGNC:7107): (marker of proliferation Ki-67) Enables protein C-terminus binding activity. Involved in regulation of chromosome segregation and regulation of mitotic nuclear division. Located in chromosome; nuclear body; and nucleolus. Colocalizes with condensed chromosome. Implicated in Crohn's disease; breast cancer; human immunodeficiency virus infectious disease; and pancreatic cancer. Biomarker of several diseases, including Barrett's esophagus; autoimmune disease of musculoskeletal system (multiple); endocrine gland cancer (multiple); gastrointestinal system cancer (multiple); and interstitial cystitis. [provided by Alliance of Genome Resources, Apr 2022]

MKI67 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06490159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKI67	NM_002417.5	c.9374T>A	p.Met3125Lys	missense_variant	14/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.8294T>A	p.Met2765Lys	missense_variant	13/14		NP_001139438.1
MKI67	XM_011539818.3	c.8342T>A	p.Met2781Lys	missense_variant	11/12		XP_011538120.1
MKI67	XM_006717864.4	c.7052T>A	p.Met2351Lys	missense_variant	3/4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.9374T>A	p.Met3125Lys	missense_variant	14/15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.8294T>A	p.Met2765Lys	missense_variant	13/14	2		ENSP00000357642.3
MKI67	ENST00000464771.1	n.587T>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.9374T>A (p.M3125K) alteration is located in exon 14 (coding exon 13) of the MKI67 gene. This alteration results from a T to A substitution at nucleotide position 9374, causing the methionine (M) at amino acid position 3125 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.8
DANN	Benign	0.84
DEOGEN2	Benign	0.0083	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.022
Sift	Benign	0.42	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.010	B;B
Vest4		0.29
MutPred		0.27		.;Gain of solvent accessibility (P = 0.0038);
MVP		0.11
MPC		0.13
ClinPred		0.034	T
GERP RS		-0.51
Varity_R		0.20
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr10-129899853;