rs200161440

Positions:

chr8-67195405-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001382391.1(CSPP1):c.3493C>T(p.Pro1165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,613,936 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 7 hom. )

Consequence

CSPP1
NM_001382391.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.28

Variant links:

Genes affected

CSPP1 (HGNC:26193): (centrosome and spindle pole associated protein 1) This gene encodes a centrosome and spindle pole associated protein. The encoded protein plays a role in cell-cycle progression and spindle organization, regulates cytokinesis, interacts with Nephrocystin 8 and is required for cilia formation. Mutations in this gene result in primary cilia abnormalities and classical Joubert syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

CSPP1 links:

ARFGEF1 (HGNC:15772): (ADP ribosylation factor guanine nucleotide exchange factor 1) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

ARFGEF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047197044).

BP6

Variant 8-67195405-C-T is Benign according to our data. Variant chr8-67195405-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 383716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67195405-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00131 (199/152268) while in subpopulation AMR AF= 0.00432 (66/15288). AF 95% confidence interval is 0.00348. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1 linkuse as main transcript	c.3493C>T	p.Pro1165Ser	missense_variant	31/31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1 linkuse as main transcript	c.3493C>T	p.Pro1165Ser	missense_variant	31/31		NM_001382391.1	ENSP00000504733

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00134

AC:

335

AN:

249478

Hom.:

AF XY:

0.00119

AC XY:

161

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000698

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.000861

AC:

1259

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000916

AC XY:

666

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.0138

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000445

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00131

AC:

199

AN:

152268

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00118

AC:

ExAC

AF:

0.00102

AC:

124

EpiCase

AF:

0.000927

EpiControl

AF:

0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	This variant is associated with the following publications: (PMID: 25616960, 26092869) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CSPP1: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CSPP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Joubert syndrome 21

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.043

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.047

Sift

Benign

0.15

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.49

P;P

Vest4

0.21

MVP

0.47

MPC

0.37

ClinPred

0.028

GERP RS

4.6

gMVP

0.068

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over