chr9-5762533-A-C

Variant names:

• chr9-5762533-A-C
• rs1543526
• NM_020829.4:c.1993-8A>C

Variant summary

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

The NM_020829.4(RIC1):​c.1993-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,610,362 control chromosomes in the GnomAD database, including 117,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9636 hom., cov: 32)
  • Exomes 𝑓: 0.38 (107831 hom.)
• Consequence: RIC1 NM_020829.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005038
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.455
• Publications: 15 publications found

Genes affected

RIC1 (HGNC:17686): (RIC1 homolog, RAB6A GEF complex partner 1) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in several processes, including positive regulation of GTPase activity; regulation of extracellular matrix constituent secretion; and retrograde transport, endosome to Golgi. Located in cytosol and membrane. Part of Ric1-Rgp1 guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ERMP1 (HGNC:23703): (endoplasmic reticulum metallopeptidase 1) Predicted to enable metal ion binding activity and metalloexopeptidase activity. Involved in cellular response to oxidative stress. Acts upstream of or within endoplasmic reticulum unfolded protein response. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-5762533-A-C is Benign according to our data. Variant chr9-5762533-A-C is described in ClinVar as Benign. ClinVar VariationId is 1300070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020829.4. 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
	RIC1	NM_020829.4	MANE Select	c.1993-8A>C		splice_region intron	N/A	NP_065880.2	Q4ADV7-1
	RIC1	NM_001206557.2		c.1882-8A>C		splice_region intron	N/A	NP_001193486.1	Q4ADV7-3
	RIC1	NM_001135920.4		c.1993-8A>C		splice_region intron	N/A	NP_001129392.2	Q4ADV7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIC1	ENST00000414202.7	TSL:5 MANE Select	c.1993-8A>C		splice_region intron	N/A	ENSP00000416696.2	Q4ADV7-1
	RIC1	ENST00000545641.5	TSL:1	c.1666-8A>C		splice_region intron	N/A	ENSP00000439488.1	H0YFN7
	RIC1	ENST00000251879.10	TSL:1	c.1993-8A>C		splice_region intron	N/A	ENSP00000251879.6	Q4ADV7-2

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52106 AN: 151882 Hom.: 9623 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.350

GnomAD2 exomes AF: 0.404 AC: 100509 AN: 248546 AF XY: 0.408

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.588

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.380 AC: 554104 AN: 1458362 Hom.: 107831 Cov.: 34 AF XY: 0.383 AC XY: 278050 AN XY: 725364

African (AFR) AF: 0.217 AC: 7230 AN: 33326

American (AMR) AF: 0.421 AC: 18600 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9234 AN: 26006

East Asian (EAS) AF: 0.610 AC: 24172 AN: 39638

South Asian (SAS) AF: 0.476 AC: 40618 AN: 85394

European-Finnish (FIN) AF: 0.392 AC: 20923 AN: 53358

Middle Eastern (MID) AF: 0.431 AC: 2479 AN: 5752

European-Non Finnish (NFE) AF: 0.368 AC: 408122 AN: 1110482

Other (OTH) AF: 0.377 AC: 22726 AN: 60252

GnomAD4 genome AF: 0.343 AC: 52163 AN: 152000 Hom.: 9636 Cov.: 32 AF XY: 0.348 AC XY: 25877 AN XY: 74294

African (AFR) AF: 0.225 AC: 9346 AN: 41468

American (AMR) AF: 0.362 AC: 5528 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1275 AN: 3468

East Asian (EAS) AF: 0.589 AC: 3052 AN: 5178

South Asian (SAS) AF: 0.495 AC: 2380 AN: 4812

European-Finnish (FIN) AF: 0.384 AC: 4041 AN: 10532

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25323 AN: 67956

Other (OTH) AF: 0.356 AC: 751 AN: 2110

Alfa AF: 0.355 Hom.: 8776

Bravo AF: 0.336

Asia WGS AF: 0.493 AC: 1713 AN: 3478

EpiCase AF: 0.383

EpiControl AF: 0.383

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.69
PhyloP100		0.46
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0020
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: rs1543526; hg19: chr9-5762533; COSMIC: COSV52605119; COSMIC: COSV52605119;