rs2290585

Variant names:

• chr8-67175044-A-G
• rs2290585
• NM_001382391.1:c.2969-252A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001413187.1(ARFGEF1):​c.*511T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 413,044 control chromosomes in the GnomAD database, including 3,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2359 hom., cov: 31)
  • Exomes 𝑓: 0.058 (871 hom.)
• Consequence: ARFGEF1 NM_001413187.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.777
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-67175044-A-G is Benign according to our data. Variant chr8-67175044-A-G is described in ClinVar as Benign. ClinVar VariationId is 1270546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413187.1. 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.2969-252A>G		intron	N/A	NP_001369320.1	A0A7I2V5W3
	ARFGEF1	NM_001413187.1		c.*511T>C		3_prime_UTR	Exon 39 of 39	NP_001400116.1
	ARFGEF1	NM_001413186.1		c.*511T>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.2969-252A>G		intron	N/A	ENSP00000504733.1	A0A7I2V5W3
	CSPP1	ENST00000262210.11	TSL:1	c.3035-252A>G		intron	N/A	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000519668.1	TSL:1	c.1919-252A>G		intron	N/A	ENSP00000430092.1	Q1MSJ5-2

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19000 AN: 151882 Hom.: 2350 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.0884

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0321

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.0576 AC: 15030 AN: 261044 Hom.: 871 Cov.: 0 AF XY: 0.0583 AC XY: 8161 AN XY: 140074

African (AFR) AF: 0.321 AC: 2525 AN: 7878

American (AMR) AF: 0.0885 AC: 1024 AN: 11566

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 325 AN: 7556

East Asian (EAS) AF: 0.0341 AC: 497 AN: 14564

South Asian (SAS) AF: 0.0833 AC: 3148 AN: 37804

European-Finnish (FIN) AF: 0.107 AC: 1296 AN: 12100

Middle Eastern (MID) AF: 0.0522 AC: 57 AN: 1092

European-Non Finnish (NFE) AF: 0.0339 AC: 5220 AN: 154162

Other (OTH) AF: 0.0655 AC: 938 AN: 14322

GnomAD4 genome AF: 0.125 AC: 19052 AN: 152000 Hom.: 2359 Cov.: 31 AF XY: 0.128 AC XY: 9504 AN XY: 74288

African (AFR) AF: 0.319 AC: 13212 AN: 41418

American (AMR) AF: 0.0883 AC: 1348 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3470

East Asian (EAS) AF: 0.0260 AC: 134 AN: 5154

South Asian (SAS) AF: 0.0877 AC: 422 AN: 4814

European-Finnish (FIN) AF: 0.127 AC: 1343 AN: 10548

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0321 AC: 2181 AN: 68006

Other (OTH) AF: 0.102 AC: 216 AN: 2112

Alfa AF: 0.0669 Hom.: 2218

Bravo AF: 0.130

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.32
DANN	Benign	0.54
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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: rs2290585; hg19: chr8-68087279;