chr1-243140091-A-G

Variant names:

• chr1-243140091-A-G
• NM_014812.3:c.4076T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014812.3(CEP170):​c.4076T>C​(p.Phe1359Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.77
• Publications: 0 publications found

Genes affected

CEP170 (HGNC:28920): (centrosomal protein 170) The product of this gene is a component of the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. During interphase, the encoded protein localizes to the sub-distal appendages of mature centrioles, which are microtubule-based structures thought to help organize centrosomes. During mitosis, the protein associates with spindle microtubules near the centrosomes. The protein interacts with and is phosphorylated by polo-like kinase 1, and functions in maintaining microtubule organization and cell morphology. The human genome contains a putative transcribed pseudogene. Several alternatively spliced transcript variants of this gene have been found, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000227230 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP170	NM_014812.3	c.4076T>C	p.Phe1359Ser	missense_variant	Exon 16 of 20	ENST00000366542.6	NP_055627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP170	ENST00000366542.6	c.4076T>C	p.Phe1359Ser	missense_variant	Exon 16 of 20	5	NM_014812.3	ENSP00000355500.1
CEP170	ENST00000366544.6	c.3782T>C	p.Phe1261Ser	missense_variant	Exon 15 of 19	5		ENSP00000355502.1
CEP170	ENST00000366543.5	c.3704T>C	p.Phe1235Ser	missense_variant	Exon 15 of 19	5		ENSP00000355501.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4076T>C (p.F1359S) alteration is located in exon 16 (coding exon 15) of the CEP170 gene. This alteration results from a T to C substitution at nucleotide position 4076, causing the phenylalanine (F) at amino acid position 1359 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;T;.;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;.;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;N;N;N;D;N;N;D
REVEL	Uncertain	0.40
Sift	Benign	0.56	T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;D;D;D;.;.
Polyphen		1.0	D;D;D;.;.;.;.;.
Vest4		0.73
MutPred		0.31		Gain of phosphorylation at F1359 (P = 0.0197);.;.;.;.;.;.;.;
MVP		0.71
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.35
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-243303393;