10-128099245-T-C

Position:

• chr10-128099245-T-C

Variant summary

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

The NM_002417.5(MKI67):​c.9716A>G​(p.Asn3239Ser) 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: -0.0330

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 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=0.028722137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKI67	NM_002417.5	c.9716A>G	p.Asn3239Ser	missense_variant	15/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.8636A>G	p.Asn2879Ser	missense_variant	14/14		NP_001139438.1
MKI67	XM_011539818.3	c.8684A>G	p.Asn2895Ser	missense_variant	12/12		XP_011538120.1
MKI67	XM_006717864.4	c.7394A>G	p.Asn2465Ser	missense_variant	4/4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.9716A>G	p.Asn3239Ser	missense_variant	15/15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.8636A>G	p.Asn2879Ser	missense_variant	14/14	2		ENSP00000357642.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Dec 10, 2024

The c.9716A>G (p.N3239S) alteration is located in exon 15 (coding exon 14) of the MKI67 gene. This alteration results from a A to G substitution at nucleotide position 9716, causing the asparagine (N) at amino acid position 3239 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.0
DANN	Benign	0.81
DEOGEN2	Benign	0.0097	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.013
Sift	Benign	0.32	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.027	B;B
Vest4		0.096
MutPred		0.12		.;Gain of phosphorylation at N3239 (P = 0.0207);
MVP		0.12
MPC		0.037
ClinPred		0.045	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.014

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr10-129897509;