rs372265885

Variant names:

• chr8-67195599-A-G
• rs372265885
• NM_001382391.1:c.*6A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001382391.1(CSPP1):​c.*6A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,611,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: CSPP1 NM_001382391.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.373
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000468 (683/1459524) while in subpopulation MID AF = 0.0023 (13/5644). AF 95% confidence interval is 0.00166. There are 2 homozygotes in GnomAdExome4. There are 398 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382391.1. 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
	CSPP1	NM_001382391.1	MANE Select	c.*6A>G		3_prime_UTR	Exon 31 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.*6A>G		3_prime_UTR	Exon 30 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.*6A>G		3_prime_UTR	Exon 29 of 29	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.*6A>G		3_prime_UTR	Exon 31 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.*6A>G		3_prime_UTR	Exon 30 of 30	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.*6A>G		3_prime_UTR	Exon 26 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000576 AC: 143 AN: 248290 AF XY: 0.000764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000468 AC: 683 AN: 1459524 Hom.: 2 Cov.: 30 AF XY: 0.000548 AC XY: 398 AN XY: 726150

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.000224 AC: 10 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00190 AC: 164 AN: 86210

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.00230 AC: 13 AN: 5644

European-Non Finnish (NFE) AF: 0.000423 AC: 469 AN: 1110048

Other (OTH) AF: 0.000365 AC: 22 AN: 60314

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000196

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		0.37
Mutation Taster		=100/0	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: rs372265885; hg19: chr8-68107834;