6-71886884-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014989.7(RIMS1):c.-140T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 869,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: RIMS1 NM_014989.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.152

Genes affected

RIMS1 (HGNC:17282): (regulating synaptic membrane exocytosis 1) The protein encoded by this gene is a RAS gene superfamily member that regulates synaptic vesicle exocytosis. This gene also plays a role in the regulation of voltage-gated calcium channels during neurotransmitter and insulin release. Mutations have suggested a role cognition and have been identified as the cause of cone-rod dystrophy type 7. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-71886884-T-C is Benign according to our data. Variant chr6-71886884-T-C is described in ClinVar as [Benign]. Clinvar id is 357825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS1	NM_014989.7	c.-140T>C		5_prime_UTR_variant	1/34	ENST00000521978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS1	ENST00000521978.6	c.-140T>C		5_prime_UTR_variant	1/34	1	NM_014989.7	A2
RIMS1	ENST00000491071.6	c.-140T>C		5_prime_UTR_variant	1/28	5
RIMS1	ENST00000697193.1	c.-140T>C		5_prime_UTR_variant	1/29			P3
RIMS1	ENST00000370419.6	n.182T>C		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00445

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000563 AC: 404 AN: 717214 Hom.: 0 Cov.: 10 AF XY: 0.000505 AC XY: 188 AN XY: 372238

Gnomad4 AFR exome AF: 0.000168

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00216

Gnomad4 EAS exome AF: 0.00321

Gnomad4 SAS exome AF: 0.0000179

Gnomad4 FIN exome AF: 0.000157

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.000571

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74426

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00446

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000601

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod dystrophy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.5
Dann	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs528494309; hg19: chr6-72596587;