chr6-72274420-C-T

Position:

chr6-72274420-C-T

Variant summary

Our verdict is Benign. Variant got -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

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=0.0056548417).

BP6

Variant 6-72274420-C-T is Benign according to our data. Variant chr6-72274420-C-T is described in ClinVar as [Benign]. Clinvar id is 260496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-72274420-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS1	NM_014989.7 linkuse as main transcript	c.3470C>T	p.Pro1157Leu	missense_variant	23/34	ENST00000521978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS1	ENST00000521978.6 linkuse as main transcript	c.3470C>T	p.Pro1157Leu	missense_variant	23/34	1	NM_014989.7	A2	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

GnomAD3 exomes

AF:

0.0211

AC:

5251

AN:

248894

Hom.:

AF XY:

0.0210

AC XY:

2837

AN XY:

135048

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 SAS exome

AF:

0.00619

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

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.0211

Gnomad4 ASJ exome

AF:

0.0281

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00605

Gnomad4 FIN exome

AF:

0.00736

Gnomad4 NFE exome

AF:

0.0335

Gnomad4 OTH exome

AF:

0.0281

GnomAD4 genome

AF:

0.0225

AC:

3424

AN:

152232

Hom.:

Cov.:

AF XY:

0.0210

AC XY:

1561

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00618

Gnomad4 AMR

AF:

0.0298

Gnomad4 ASJ

AF:

0.0257

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.0340

Gnomad4 OTH

AF:

0.0302

Alfa

AF:

0.0306

Hom.:

140

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D

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

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

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