6-72392740-C-T

Position:

• chr6-72392740-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014989.7(RIMS1):​c.4548C>T​(p.Phe1516Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,611,926 control chromosomes in the GnomAD database, including 43,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3362 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40117 hom.)
• Consequence: RIMS1 NM_014989.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35

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]

RIMS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 6-72392740-C-T is Benign according to our data. Variant chr6-72392740-C-T is described in ClinVar as [Benign]. Clinvar id is 260498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIMS1	NM_014989.7	c.4548C>T	p.Phe1516Phe	synonymous_variant	31/34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6	c.4548C>T	p.Phe1516Phe	synonymous_variant	31/34	1	NM_014989.7	ENSP00000428417.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30524 AN: 151870 Hom.: 3360 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.209 AC: 52052 AN: 249168 Hom.: 6335 AF XY: 0.220 AC XY: 29737 AN XY: 135162

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0160

Gnomad SAS exome AF: 0.301

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.228 AC: 332575 AN: 1459938 Hom.: 40117 Cov.: 32 AF XY: 0.231 AC XY: 167619 AN XY: 726374

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.0168

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.201 AC: 30556 AN: 151988 Hom.: 3362 Cov.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74290

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.0177

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.209

Alfa AF: 0.227 Hom.: 2012

Bravo AF: 0.189

Asia WGS AF: 0.153 AC: 535 AN: 3478

EpiCase AF: 0.245

EpiControl AF: 0.241

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.28
CADD	Benign	10
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2815738; hg19: chr6-73102442;