Genetic Variant NM_002417.5:c.3124G>A (chr10-128108716-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002417.5(MKI67):c.3124G>A(p.Gly1042Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,614,028 control chromosomes in the GnomAD database, including 47,492 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 0.21 ( 3894 hom., cov: 33)

Exomes 𝑓: 0.24 ( 43598 hom. )

Consequence

MKI67
NM_002417.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.36

Publications

22 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0050908625).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5 link	c.3124G>A	p.Gly1042Ser	missense_variant	Exon 13 of 15	ENST00000368654.8	NP_002408.3	P46013-1
MKI67	NM_001145966.2 link	c.2044G>A	p.Gly682Ser	missense_variant	Exon 12 of 14		NP_001139438.1	P46013-2
MKI67	XM_011539818.3 link	c.2092G>A	p.Gly698Ser	missense_variant	Exon 10 of 12		XP_011538120.1
MKI67	XM_006717864.4 link	c.802G>A	p.Gly268Ser	missense_variant	Exon 2 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8 link	c.3124G>A	p.Gly1042Ser	missense_variant	Exon 13 of 15	2	NM_002417.5	ENSP00000357643.3		P46013-1
MKI67	ENST00000368653.7 link	c.2044G>A	p.Gly682Ser	missense_variant	Exon 12 of 14	2		ENSP00000357642.3		P46013-2

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32677

AN:

152038

Hom.:

3886

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.294

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.245

AC:

61483

AN:

251406

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.305

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.288

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.242

AC:

353424

AN:

1461872

Hom.:

43598

Cov.:

AF XY:

0.241

AC XY:

175463

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.121

AC:

4066

AN:

33480

American (AMR)

AF:

0.321

AC:

14335

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

7781

AN:

26136

East Asian (EAS)

AF:

0.159

AC:

6317

AN:

39700

South Asian (SAS)

AF:

0.210

AC:

18154

AN:

86258

European-Finnish (FIN)

AF:

0.291

AC:

15563

AN:

53418

Middle Eastern (MID)

AF:

0.270

AC:

1558

AN:

5768

European-Non Finnish (NFE)

AF:

0.244

AC:

271432

AN:

1111992

Other (OTH)

AF:

0.235

AC:

14218

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18715

37429

56144

74858

93573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9214

18428

27642

36856

46070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.215

AC:

32696

AN:

152156

Hom.:

3894

Cov.:

AF XY:

0.217

AC XY:

16168

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.128

AC:

5327

AN:

41522

American (AMR)

AF:

0.277

AC:

4244

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1030

AN:

3470

East Asian (EAS)

AF:

0.128

AC:

660

AN:

5160

South Asian (SAS)

AF:

0.203

AC:

978

AN:

4822

European-Finnish (FIN)

AF:

0.294

AC:

3108

AN:

10574

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16449

AN:

67992

Other (OTH)

AF:

0.245

AC:

518

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1330

2660

3990

5320

6650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.237

Hom.:

15915

Bravo

AF:

0.215

TwinsUK

AF:

0.238

AC:

883

ALSPAC

AF:

0.244

AC:

941

ESP6500AA

AF:

0.131

AC:

576

ESP6500EA

AF:

0.247

AC:

2128

ExAC

AF:

0.239

AC:

29014

Asia WGS

AF:

0.153

AC:

532

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.259

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.24

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0091

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.42

.;N

PhyloP100

-1.4

PrimateAI

Benign

0.20

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.053

Sift

Benign

0.81

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.97

D;P

Vest4

0.030

MPC

0.25

ClinPred

0.0023

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.074

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over