rs114505309

Variant names:

• chr6-72182680-G-A
• rs114505309
• NM_014989.7:c.1209G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014989.7(RIMS1):​c.1209G>A​(p.Ala403Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,445,990 control chromosomes in the GnomAD database, including 91,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6872 hom., cov: 32)
  • Exomes 𝑓: 0.36 (85013 hom.)
• Consequence: RIMS1 NM_014989.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.39

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-72182680-G-A is Benign according to our data. Variant chr6-72182680-G-A is described in ClinVar as [Benign]. Clinvar id is 95656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-72182680-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMS1	NM_014989.7	c.1209G>A	p.Ala403Ala	synonymous_variant	Exon 6 of 34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6	c.1209G>A	p.Ala403Ala	synonymous_variant	Exon 6 of 34	1	NM_014989.7	ENSP00000428417.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42418 AN: 151314 Hom.: 6879 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.455 AC: 26400 AN: 57980 Hom.: 5513 AF XY: 0.450 AC XY: 14459 AN XY: 32134

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.324

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.358 AC: 463780 AN: 1294568 Hom.: 85013 Cov.: 38 AF XY: 0.358 AC XY: 226865 AN XY: 634486

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.135

Gnomad4 SAS exome AF: 0.317

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.372

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.280 AC: 42413 AN: 151422 Hom.: 6872 Cov.: 32 AF XY: 0.282 AC XY: 20850 AN XY: 73990

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.285

Alfa AF: 0.332 Hom.: 1139

Bravo AF: 0.266

Asia WGS AF: 0.201 AC: 695 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 7 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Uncertain	0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs114505309; hg19: chr6-72892383; COSMIC: COSV53439155; COSMIC: COSV53439155;