1-243156315-A-T

Position:

• chr1-243156315-A-T

Variant summary

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

The NM_014812.3(CEP170):​c.3817T>A​(p.Ser1273Thr) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

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=0.035875708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP170	NM_014812.3	c.3817T>A	p.Ser1273Thr	missense_variant	14/20	ENST00000366542.6	NP_055627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP170	ENST00000366542.6	c.3817T>A	p.Ser1273Thr	missense_variant	14/20	5	NM_014812.3	ENSP00000355500.1
CEP170	ENST00000366544.5	c.3523T>A	p.Ser1175Thr	missense_variant	13/19	5		ENSP00000355502.1
CEP170	ENST00000366543.5	c.3415T>A	p.Ser1139Thr	missense_variant	13/19	5		ENSP00000355501.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.94e-7 AC: 1 AN: 1441180 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Mar 30, 2024

The c.3817T>A (p.S1273T) alteration is located in exon 14 (coding exon 13) of the CEP170 gene. This alteration results from a T to A substitution at nucleotide position 3817, causing the serine (S) at amino acid position 1273 to be replaced by a threonine (T). 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	0.063
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.0052	T;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.85	.;.;.;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.0	N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.65	T;T;T;T
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.16
MutPred		0.14		Loss of phosphorylation at S1273 (P = 0.0644);.;.;.;
MVP		0.19
ClinPred		0.070	T
GERP RS		2.3
Varity_R		0.031
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs1281087050; hg19: chr1-243319617;