6-71886897-G-A

Position:

• chr6-71886897-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014989.7(RIMS1):​c.-127G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,070,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: RIMS1 NM_014989.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS2: High AC in GnomAd4 at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIMS1	NM_014989.7	c.-127G>A		5_prime_UTR_variant	1/34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6	c.-127G>A		5_prime_UTR_variant	1/34	1	NM_014989.7	ENSP00000428417.1
RIMS1	ENST00000697193.1	c.-127G>A		5_prime_UTR_variant	1/29			ENSP00000513179.1
RIMS1	ENST00000491071.6	c.-127G>A		5_prime_UTR_variant	1/28	5		ENSP00000430101.1
RIMS1	ENST00000370419.6	n.195G>A		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00172 AC: 1575 AN: 918124 Hom.: 2 Cov.: 12 AF XY: 0.00165 AC XY: 771 AN XY: 467278

Gnomad4 AFR exome AF: 0.000367

Gnomad4 AMR exome AF: 0.000911

Gnomad4 ASJ exome AF: 0.00231

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74454

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod dystrophy 7 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs371884894; hg19: chr6-72596600;