rs116476753

chr6-72179846-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014989.7(RIMS1):c.743C>T(p.Ser248Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,607,778 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S248S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (226 hom.)
• Consequence: RIMS1 NM_014989.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033492744).
• BP6: Variant 6-72179846-C-T is Benign according to our data. Variant chr6-72179846-C-T is described in ClinVar as [Benign]. Clinvar id is 260501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0163 (2481/152256) while in subpopulation SAS AF= 0.055 (265/4820). AF 95% confidence interval is 0.0495. There are 65 homozygotes in gnomad4. There are 1284 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2472 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS1	NM_014989.7	c.743C>T	p.Ser248Leu	missense_variant	5/34	ENST00000521978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS1	ENST00000521978.6	c.743C>T	p.Ser248Leu	missense_variant	5/34	1	NM_014989.7	A2

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2472 AN: 152138 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0483

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0135 AC: 3270 AN: 242458 Hom.: 88 AF XY: 0.0145 AC XY: 1909 AN XY: 131642

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00402

Gnomad EAS exome AF: 0.0502

Gnomad SAS exome AF: 0.0497

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.00567 AC: 8248 AN: 1455522 Hom.: 226 Cov.: 33 AF XY: 0.00672 AC XY: 4865 AN XY: 723608

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.0474

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.0163 AC: 2481 AN: 152256 Hom.: 65 Cov.: 32 AF XY: 0.0172 AC XY: 1284 AN XY: 74436

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0479

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00525 Hom.: 21

Bravo AF: 0.0161

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0348 AC: 144

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.0142 AC: 1713

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.000439

EpiControl AF: 0.000476

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	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	- -

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
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
MetaRNN	Benign	0.0033	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.052	T;T;D;D;D;D;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T
Polyphen		0.77	.;.;.;.;P;.;.
Vest4		0.095
MPC		0.53
ClinPred		0.020	T
GERP RS		5.0
Varity_R		0.065
gMVP		0.20

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: rs116476753; hg19: chr6-72889549; COSMIC: COSV53460910; COSMIC: COSV53460910;