rs116476753

Positions:

chr6-72179846-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000521978.6(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S248W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 65 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 226 hom. )

Consequence

RIMS1
ENST00000521978.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 2481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIMS1	NM_014989.7 linkuse as main transcript	c.743C>T	p.Ser248Leu	missense_variant	5/34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6 linkuse as main transcript	c.743C>T	p.Ser248Leu	missense_variant	5/34	1	NM_014989.7	ENSP00000428417	A2	Q86UR5-1

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2472

AN:

152138

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0145

AC XY:

1909

AN XY:

131642

show subpopulations

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.:

AF XY:

0.00672

AC XY:

4865

AN XY:

723608

show subpopulations

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.:

Cov.:

AF XY:

0.0172

AC XY:

1284

AN XY:

74436

show subpopulations

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.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0348

AC:

144

ESP6500EA

AF:

0.000356

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;.;.;T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.60

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over