NM_014812.3:c.3910A>G

Variant names:

• chr1-243156222-T-C
• rs1413359447
• NM_014812.3:c.3910A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014812.3(CEP170):​c.3910A>G​(p.Arg1304Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 150,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R1304M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: CEP170 NM_014812.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• 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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014812.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP170	NM_014812.3	MANE Select	c.3910A>G	p.Arg1304Gly	missense splice_region	Exon 14 of 20	NP_055627.2	Q5SW79-1
	CEP170	NM_001042404.2		c.3616A>G	p.Arg1206Gly	missense splice_region	Exon 13 of 19	NP_001035863.1	Q5SW79-3
	CEP170	NM_001042405.2		c.3508A>G	p.Arg1170Gly	missense splice_region	Exon 13 of 19	NP_001035864.1	Q5SW79-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP170	ENST00000366542.6	TSL:5 MANE Select	c.3910A>G	p.Arg1304Gly	missense splice_region	Exon 14 of 20	ENSP00000355500.1	Q5SW79-1
	CEP170	ENST00000366544.6	TSL:5	c.3616A>G	p.Arg1206Gly	missense splice_region	Exon 13 of 19	ENSP00000355502.1	Q5SW79-3
	CEP170	ENST00000366543.5	TSL:5	c.3508A>G	p.Arg1170Gly	missense splice_region	Exon 13 of 19	ENSP00000355501.1	Q5SW79-2

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150904 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150904 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73518

African (AFR) AF: 0.00 AC: 0 AN: 40964

American (AMR) AF: 0.00 AC: 0 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67852

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.39		Gain of helix (P = 0.0496)
MVP		0.69
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.81
gMVP		0.63
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.070		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: rs1413359447; hg19: chr1-243319524;