NM_014989.7:c.3470C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014989.7(RIMS1):c.3470C>T(p.Pro1157Leu) variant causes a missense change. The variant allele was found at a frequency of 0.028 in 1,612,252 control chromosomes in the GnomAD database, including 741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1157P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.022 ( 69 hom., cov: 32)

Exomes 𝑓: 0.029 ( 672 hom. )

Consequence

RIMS1
NM_014989.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.95

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy 7
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Illumina

RIMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056548417).

BP6

Variant 6-72274420-C-T is Benign according to our data. Variant chr6-72274420-C-T is described in ClinVar as Benign. ClinVar VariationId is 260496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0225 (3424/152232) while in subpopulation NFE AF = 0.034 (2314/68010). AF 95% confidence interval is 0.0329. There are 69 homozygotes in GnomAd4. There are 1561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMS1	NM_014989.7 link	c.3470C>T	p.Pro1157Leu	missense_variant	Exon 23 of 34	ENST00000521978.6	NP_055804.2	Q86UR5-1Q3ZCW0B7Z7W2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6 link	c.3470C>T	p.Pro1157Leu	missense_variant	Exon 23 of 34	1	NM_014989.7	ENSP00000428417.1		Q86UR5-1

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3426

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0257

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0340

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0211

AC:

5251

AN:

248894

AF XY:

0.0210

show subpopulations

Gnomad AFR exome

AF:

0.00557

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00599

Gnomad NFE exome

AF:

0.0329

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0286

AC:

41797

AN:

1460020

Hom.:

672

Cov.:

AF XY:

0.0280

AC XY:

20345

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.00502

AC:

168

AN:

33466

American (AMR)

AF:

0.0211

AC:

945

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

734

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00605

AC:

521

AN:

86134

European-Finnish (FIN)

AF:

0.00736

AC:

393

AN:

53378

Middle Eastern (MID)

AF:

0.0202

AC:

116

AN:

5734

European-Non Finnish (NFE)

AF:

0.0335

AC:

37227

AN:

1110540

Other (OTH)

AF:

0.0281

AC:

1693

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

1804

3609

5413

7218

9022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1356

2712

4068

5424

6780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0225

AC:

3424

AN:

152232

Hom.:

Cov.:

AF XY:

0.0210

AC XY:

1561

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00618

AC:

257

AN:

41554

American (AMR)

AF:

0.0298

AC:

455

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00394

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0340

AC:

2314

AN:

68010

Other (OTH)

AF:

0.0302

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0292

Hom.:

247

Bravo

AF:

0.0245

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00708

AC:

ESP6500EA

AF:

0.0333

AC:

275

ExAC

AF:

0.0211

AC:

2548

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0325

EpiControl

AF:

0.0338

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 7

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

6.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.0

N;D

REVEL

Benign

0.25

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

.;D

Vest4

0.33

MPC

0.64

ClinPred

0.017

GERP RS

5.6

Varity_R

0.30

gMVP

0.65

Mutation Taster

=45/55

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over