rs1808140

Variant names:

• chr8-67190742-T-C
• rs1808140
• NM_001382391.1:c.3313T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000678616.1(CSPP1):​c.3313T>C​(p.Trp1105Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,610,886 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (80 hom., cov: 32)
  • Exomes 𝑓: 0.012 (430 hom.)
• Consequence: CSPP1 ENST00000678616.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43
• Publications: 12 publications found

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]

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 Gene-Disease associations (from GenCC):

• developmental delay, impaired speech, and behavioral abnormalities, with or without seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013003945).
• BP6: Variant 8-67190742-T-C is Benign according to our data. Variant chr8-67190742-T-C is described in ClinVar as Benign. ClinVar VariationId is 379419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0222 (3375/152242) while in subpopulation SAS AF = 0.0462 (223/4824). AF 95% confidence interval is 0.0413. There are 80 homozygotes in GnomAd4. There are 2004 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 80 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000678616.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	NM_001382391.1	MANE Select	c.3313T>C	p.Trp1105Arg	missense	Exon 29 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.3379T>C	p.Trp1127Arg	missense	Exon 28 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.3298T>C	p.Trp1100Arg	missense	Exon 27 of 29	NP_079066.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.3313T>C	p.Trp1105Arg	missense	Exon 29 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.3379T>C	p.Trp1127Arg	missense	Exon 28 of 30	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.2263T>C	p.Trp755Arg	missense	Exon 24 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3372 AN: 152124 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0223 AC: 5559 AN: 249492 AF XY: 0.0228

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00959

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.0973

Gnomad NFE exome AF: 0.00718

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0120 AC: 17543 AN: 1458644 Hom.: 430 Cov.: 29 AF XY: 0.0129 AC XY: 9380 AN XY: 725942

African (AFR) AF: 0.0359 AC: 1198 AN: 33410

American (AMR) AF: 0.00993 AC: 444 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00682 AC: 178 AN: 26118

East Asian (EAS) AF: 0.0242 AC: 959 AN: 39688

South Asian (SAS) AF: 0.0432 AC: 3726 AN: 86182

European-Finnish (FIN) AF: 0.0866 AC: 4626 AN: 53416

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5764

European-Non Finnish (NFE) AF: 0.00486 AC: 5386 AN: 1109064

Other (OTH) AF: 0.0153 AC: 925 AN: 60290

GnomAD4 genome AF: 0.0222 AC: 3375 AN: 152242 Hom.: 80 Cov.: 32 AF XY: 0.0269 AC XY: 2004 AN XY: 74434

African (AFR) AF: 0.0344 AC: 1428 AN: 41526

American (AMR) AF: 0.0106 AC: 162 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5186

South Asian (SAS) AF: 0.0462 AC: 223 AN: 4824

European-Finnish (FIN) AF: 0.101 AC: 1067 AN: 10590

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00537 AC: 365 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.00907 Hom.: 54

Bravo AF: 0.0156

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.0367 AC: 142

ESP6500EA AF: 0.00399 AC: 33

ExAC AF: 0.0216 AC: 2617

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 21 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.9
DANN	Benign	0.66
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.019
Sift	Benign	0.37	T
Sift4G	Benign	0.38	T
Polyphen		0.022	B
Vest4		0.071
MPC		0.24
ClinPred		0.0019	T
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.019
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1808140; hg19: chr8-68102977; COSMIC: COSV107262976;