chr10-128102737-G-T

Position:

• chr10-128102737-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002417.5(MKI67):​c.9103C>A​(p.Pro3035Thr) 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. 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. P3035L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.287

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10828224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKI67	NM_002417.5	c.9103C>A	p.Pro3035Thr	missense_variant	13/15	ENST00000368654.8
MKI67	NM_001145966.2	c.8023C>A	p.Pro2675Thr	missense_variant	12/14
MKI67	XM_011539818.3	c.8071C>A	p.Pro2691Thr	missense_variant	10/12
MKI67	XM_006717864.4	c.6781C>A	p.Pro2261Thr	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKI67	ENST00000368654.8	c.9103C>A	p.Pro3035Thr	missense_variant	13/15	2	NM_002417.5	P2
MKI67	ENST00000368653.7	c.8023C>A	p.Pro2675Thr	missense_variant	12/14	2		A2
MKI67	ENST00000464771.1	n.392C>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

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

Mar 31, 2023

The c.9103C>A (p.P3035T) alteration is located in exon 13 (coding exon 12) of the MKI67 gene. This alteration results from a C to A substitution at nucleotide position 9103, causing the proline (P) at amino acid position 3035 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.0
DANN	Benign	0.92
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.061
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.74	P;P
Vest4		0.16
MutPred		0.31		.;Loss of loop (P = 0.0203);
MVP		0.19
MPC		0.31
ClinPred		0.37	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.061

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-129901001;