chr10-128101514-G-C

Variant names:

• chr10-128101514-G-C
• rs11106
• NM_002417.5:c.9449C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002417.5(MKI67):​c.9449C>G​(p.Thr3150Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,613,824 control chromosomes in the GnomAD database, including 147,887 homozygotes. 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: 𝑓 0.44 (14532 hom., cov: 33)
  • Exomes 𝑓: 0.43 (133355 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6834156E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.9449C>G	p.Thr3150Ser	missense_variant	Exon 14 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.8369C>G	p.Thr2790Ser	missense_variant	Exon 13 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.8417C>G	p.Thr2806Ser	missense_variant	Exon 11 of 12		XP_011538120.1
MKI67	XM_006717864.4	c.7127C>G	p.Thr2376Ser	missense_variant	Exon 3 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.9449C>G	p.Thr3150Ser	missense_variant	Exon 14 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.8369C>G	p.Thr2790Ser	missense_variant	Exon 13 of 14	2		ENSP00000357642.3
MKI67	ENST00000464771.1	n.662C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66178 AN: 151858 Hom.: 14527 Cov.: 33

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.438 AC: 110223 AN: 251388 AF XY: 0.430

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.420

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.439

GnomAD4 exome AF: 0.426 AC: 622698 AN: 1461848 Hom.: 133355 Cov.: 59 AF XY: 0.423 AC XY: 307932 AN XY: 727228

African (AFR) AF: 0.440 AC: 14728 AN: 33478

American (AMR) AF: 0.546 AC: 24416 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 13162 AN: 26136

East Asian (EAS) AF: 0.443 AC: 17591 AN: 39700

South Asian (SAS) AF: 0.353 AC: 30435 AN: 86258

European-Finnish (FIN) AF: 0.423 AC: 22588 AN: 53412

Middle Eastern (MID) AF: 0.436 AC: 2517 AN: 5768

European-Non Finnish (NFE) AF: 0.424 AC: 471495 AN: 1111976

Other (OTH) AF: 0.427 AC: 25766 AN: 60396

GnomAD4 genome AF: 0.436 AC: 66211 AN: 151976 Hom.: 14532 Cov.: 33 AF XY: 0.436 AC XY: 32400 AN XY: 74276

African (AFR) AF: 0.448 AC: 18564 AN: 41436

American (AMR) AF: 0.505 AC: 7718 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1724 AN: 3466

East Asian (EAS) AF: 0.403 AC: 2077 AN: 5156

South Asian (SAS) AF: 0.343 AC: 1655 AN: 4820

European-Finnish (FIN) AF: 0.421 AC: 4441 AN: 10538

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28394 AN: 67952

Other (OTH) AF: 0.456 AC: 962 AN: 2108

Alfa AF: 0.438 Hom.: 4673

Bravo AF: 0.447

TwinsUK AF: 0.416 AC: 1542

ALSPAC AF: 0.429 AC: 1655

ESP6500AA AF: 0.445 AC: 1961

ESP6500EA AF: 0.425 AC: 3659

ExAC AF: 0.432 AC: 52407

Asia WGS AF: 0.398 AC: 1387 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.435

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.055
DANN	Benign	0.14
DEOGEN2	Benign	0.0026	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.000027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	.;N
PhyloP100		-1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.96	N;N
REVEL	Benign	0.0090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.025
MutPred		0.074		.;Loss of methylation at K3153 (P = 0.0982);
MPC		0.039
ClinPred		0.0036	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.019
Mutation Taster		=99/1	polymorphism (auto)

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: rs11106; hg19: chr10-129899778; COSMIC: COSV64074529;