1-179992199-C-G

Variant names:

• chr1-179992199-C-G
• rs745381316
• NM_014810.5:c.373C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014810.5(CEP350):​c.373C>G​(p.Arg125Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,946 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CEP350 NM_014810.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31
• Publications: 4 publications found

Genes affected

CEP350 (HGNC:24238): (centrosomal protein 350) The product of this gene is a large protein with a CAP-Gly domain typically found in cytoskeleton-associated proteins. The encoded protein primarily localizes to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. The encoded protein directly interacts with another large centrosomal protein and is required to anchor microtubules at the centrosome. It is also implicated in the regulation of a class of nuclear hormone receptors in the nucleus. Several alternatively spliced transcript variants have been found, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000303101 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26127303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP350	NM_014810.5	c.373C>G	p.Arg125Gly	missense_variant	Exon 5 of 38	ENST00000367607.8	NP_055625.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP350	ENST00000367607.8	c.373C>G	p.Arg125Gly	missense_variant	Exon 5 of 38	1	NM_014810.5	ENSP00000356579.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000256 AC: 3 AN: 117148 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345946 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 663966

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27668

American (AMR) AF: 0.0000489 AC: 1 AN: 20462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23290

East Asian (EAS) AF: 0.00 AC: 0 AN: 32940

South Asian (SAS) AF: 0.00 AC: 0 AN: 68670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062148

Other (OTH) AF: 0.00 AC: 0 AN: 55568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000255 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373C>G (p.R125G) alteration is located in exon 5 (coding exon 4) of the CEP350 gene. This alteration results from a C to G substitution at nucleotide position 373, causing the arginine (R) at amino acid position 125 to be replaced by a glycine (G). 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	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M;.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.62
MutPred		0.32		Loss of MoRF binding (P = 0.0093);.;.;
MVP		0.60
MPC		0.44
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.25
Mutation Taster		=55/45	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: rs745381316; hg19: chr1-179961334;