1-179992200-G-A

Variant names:

• chr1-179992200-G-A
• rs371166728
• NM_014810.5:c.374G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014810.5(CEP350):​c.374G>A​(p.Arg125His) variant causes a missense change. The variant allele was found at a frequency of 0.0000193 in 1,502,436 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. R125G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CEP350 NM_014810.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10907599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP350	NM_014810.5	c.374G>A	p.Arg125His	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.374G>A	p.Arg125His	missense_variant	Exon 5 of 38	1	NM_014810.5	ENSP00000356579.3

Frequencies

GnomAD3 genomes AF: 0.0000991 AC: 15 AN: 151378 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000506 AC: 6 AN: 118518 AF XY: 0.0000473

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.0000994

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 14 AN: 1351058 Hom.: 0 Cov.: 31 AF XY: 0.00000750 AC XY: 5 AN XY: 666606

African (AFR) AF: 0.000108 AC: 3 AN: 27738

American (AMR) AF: 0.0000480 AC: 1 AN: 20842

Ashkenazi Jewish (ASJ) AF: 0.0000853 AC: 2 AN: 23448

East Asian (EAS) AF: 0.00 AC: 0 AN: 33292

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49780

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5544

European-Non Finnish (NFE) AF: 0.00000563 AC: 6 AN: 1064956

Other (OTH) AF: 0.00 AC: 0 AN: 55836

GnomAD4 genome AF: 0.0000991 AC: 15 AN: 151378 Hom.: 0 Cov.: 31 AF XY: 0.0000541 AC XY: 4 AN XY: 73870

African (AFR) AF: 0.000364 AC: 15 AN: 41156

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000426 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>A (p.R125H) alteration is located in exon 5 (coding exon 4) of the CEP350 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a histidine (H). 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	0.10
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;T;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.25
MVP		0.48
MPC		0.37
ClinPred		0.19	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.16
Mutation Taster		=63/37	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: rs371166728; hg19: chr1-179961335;