chr6-72179846-C-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.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. 13/21 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
NM_014989.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.80

Publications

8 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, Illumina, Ambry Genetics, 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=0.0033492744).

BP6

Variant 6-72179846-C-T is Benign according to our data. Variant chr6-72179846-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2481 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014989.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	NM_014989.7	MANE Select	c.743C>T	p.Ser248Leu	missense	Exon 5 of 34	NP_055804.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.743C>T	p.Ser248Leu	missense	Exon 5 of 34	ENSP00000428417.1	Q86UR5-1
RIMS1	ENST00000264839.11	TSL:5	c.743C>T	p.Ser248Leu	missense	Exon 5 of 30	ENSP00000264839.7	Q86UR5-4
RIMS1	ENST00000697193.1		c.743C>T	p.Ser248Leu	missense	Exon 5 of 29	ENSP00000513179.1	A0A8V8TKU9

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

GnomAD2 exomes

AF:

0.0135

AC:

3270

AN:

242458

AF XY:

0.0145

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 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

African (AFR)

AF:

0.0456

AC:

1520

AN:

33300

American (AMR)

AF:

0.00226

AC:

100

AN:

44208

Ashkenazi Jewish (ASJ)

AF:

0.00397

AC:

102

AN:

25698

East Asian (EAS)

AF:

0.0429

AC:

1700

AN:

39642

South Asian (SAS)

AF:

0.0474

AC:

4053

AN:

85478

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00471

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000205

AC:

227

AN:

1108380

Other (OTH)

AF:

0.00863

AC:

518

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

396

793

1189

1586

1982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.0163

AC:

2481

AN:

152256

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1284

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0447

AC:

1857

AN:

41544

American (AMR)

AF:

0.00477

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.0479

AC:

248

AN:

5182

South Asian (SAS)

AF:

0.0550

AC:

265

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68026

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

249

373

498

622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00633

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cone-rod dystrophy 7 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.060

Sift

Benign

0.052

Sift4G

Benign

0.21

Polyphen

0.77

Vest4

0.095

MPC

0.53

ClinPred

0.020

GERP RS

5.0

Varity_R

0.065

gMVP

0.20

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over