1-243140049-T-C

Variant names:

• chr1-243140049-T-C
• rs774260650
• NM_014812.3:c.4118A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014812.3(CEP170):​c.4118A>G​(p.His1373Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1796433).
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP170	NM_014812.3	c.4118A>G	p.His1373Arg	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.4118A>G	p.His1373Arg	missense_variant	Exon 16 of 20	5	NM_014812.3	ENSP00000355500.1
CEP170	ENST00000366544.6	c.3824A>G	p.His1275Arg	missense_variant	Exon 15 of 19	5		ENSP00000355502.1
CEP170	ENST00000366543.5	c.3746A>G	p.His1249Arg	missense_variant	Exon 15 of 19	5		ENSP00000355501.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249212 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4118A>G (p.H1373R) alteration is located in exon 16 (coding exon 15) of the CEP170 gene. This alteration results from a A to G substitution at nucleotide position 4118, causing the histidine (H) at amino acid position 1373 to be replaced by an arginine (R). 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	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.043	T;.;.;.;T;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;.;.;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;D
REVEL	Benign	0.061
Sift	Benign	0.030	D;T;T;T;T;T;T;D
Sift4G	Benign	0.20	T;T;T;T;T;T;.;.
Polyphen		0.049	B;P;P;.;.;.;.;.
Vest4		0.47
MutPred		0.20		Gain of MoRF binding (P = 0.0206);.;.;.;.;.;.;.;
MVP		0.35
ClinPred		0.24	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.16
Mutation Taster		=74/26	polymorphism

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: rs774260650; hg19: chr1-243303351;