chr8-67175293-C-G

Variant names:

• chr8-67175293-C-G
• rs1470495151
• NM_001382391.1:c.2969-3C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001382391.1(CSPP1):​c.2969-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSPP1 NM_001382391.1 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.796
• 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• schizophrenia

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.2969-3C>G		splice_region intron	N/A	NP_001369320.1	A0A7I2V5W3
	ARFGEF1	NM_001413187.1		c.*262G>C		3_prime_UTR	Exon 39 of 39	NP_001400116.1
	ARFGEF1	NM_001413186.1		c.*262G>C		3_prime_UTR	Exon 39 of 39	NP_001400115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2969-3C>G		splice_region intron	N/A	ENSP00000504733.1	A0A7I2V5W3
	CSPP1	ENST00000262210.11	TSL:1	c.3035-3C>G		splice_region intron	N/A	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000519668.1	TSL:1	c.1919-3C>G		splice_region intron	N/A	ENSP00000430092.1	Q1MSJ5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.91
PhyloP100		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.86		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1470495151; hg19: chr8-68087528;