rs3740423

Variant names:

• chr10-128107632-T-A
• rs3740423
• NM_002417.5:c.4208A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-128107632-T-A
• chr10-128107632-T-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.4208A>T​(p.Glu1403Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,910 control chromosomes in the GnomAD database, including 27,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.14 (2063 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25167 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592
• Publications: 21 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=0.005635649).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.4208A>T	p.Glu1403Val	missense_variant	Exon 13 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.3128A>T	p.Glu1043Val	missense_variant	Exon 12 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.3176A>T	p.Glu1059Val	missense_variant	Exon 10 of 12		XP_011538120.1
MKI67	XM_006717864.4	c.1886A>T	p.Glu629Val	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	c.4208A>T	p.Glu1403Val	missense_variant	Exon 13 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.3128A>T	p.Glu1043Val	missense_variant	Exon 12 of 14	2		ENSP00000357642.3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22000 AN: 151908 Hom.: 2056 Cov.: 32

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.195 AC: 48916 AN: 251414 AF XY: 0.195

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.182 AC: 265511 AN: 1461884 Hom.: 25167 Cov.: 85 AF XY: 0.183 AC XY: 132909 AN XY: 727246

African (AFR) AF: 0.0290 AC: 970 AN: 33480

American (AMR) AF: 0.283 AC: 12671 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6591 AN: 26136

East Asian (EAS) AF: 0.159 AC: 6320 AN: 39700

South Asian (SAS) AF: 0.197 AC: 16979 AN: 86258

European-Finnish (FIN) AF: 0.222 AC: 11851 AN: 53420

Middle Eastern (MID) AF: 0.208 AC: 1201 AN: 5768

European-Non Finnish (NFE) AF: 0.178 AC: 198270 AN: 1112002

Other (OTH) AF: 0.176 AC: 10658 AN: 60396

GnomAD4 genome AF: 0.145 AC: 22008 AN: 152026 Hom.: 2063 Cov.: 32 AF XY: 0.148 AC XY: 11014 AN XY: 74284

African (AFR) AF: 0.0341 AC: 1416 AN: 41522

American (AMR) AF: 0.220 AC: 3357 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3468

East Asian (EAS) AF: 0.129 AC: 662 AN: 5144

South Asian (SAS) AF: 0.189 AC: 908 AN: 4804

European-Finnish (FIN) AF: 0.220 AC: 2318 AN: 10532

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11890 AN: 67986

Other (OTH) AF: 0.178 AC: 376 AN: 2112

Alfa AF: 0.155 Hom.: 733

Bravo AF: 0.143

TwinsUK AF: 0.180 AC: 669

ALSPAC AF: 0.180 AC: 692

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.183 AC: 1574

ExAC AF: 0.189 AC: 22920

Asia WGS AF: 0.143 AC: 496 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.199

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	.;L
PhyloP100		-0.59
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.022
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.14
MPC		0.30
ClinPred		0.029	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.23
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: rs3740423; hg19: chr10-129905896; COSMIC: COSV64073379; COSMIC: COSV64073379;