rs41265501

Variant names:

• chr6-72274420-C-T
• rs41265501
• NM_014989.7:c.3470C>T
• RIMS1 p.Pro1157Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.95
• Publications: 12 publications found

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: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

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.

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.3470C>T	p.Pro1157Leu	missense	Exon 23 of 34	NP_055804.2
	RIMS1	NM_001350433.2		c.1700C>T	p.Pro567Leu	missense	Exon 16 of 26	NP_001337362.1
	RIMS1	NM_001350415.2		c.1697C>T	p.Pro566Leu	missense	Exon 16 of 26	NP_001337344.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.3470C>T	p.Pro1157Leu	missense	Exon 23 of 34	ENSP00000428417.1	Q86UR5-1
	RIMS1	ENST00000425662.6	TSL:1	c.1385+8371C>T		intron	N/A	ENSP00000411235.2	Q86UR5-10
	RIMS1	ENST00000370420.8	TSL:1	c.881+8371C>T		intron	N/A	ENSP00000359448.4	A0A0C4DFV1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3426 AN: 152114 Hom.: 69 Cov.: 32

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

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.: 29 AF XY: 0.0280 AC XY: 20345 AN XY: 726380

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: 0 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

GnomAD4 genome AF: 0.0225 AC: 3424 AN: 152232 Hom.: 69 Cov.: 32 AF XY: 0.0210 AC XY: 1561 AN XY: 74434

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: 89 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4820

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0340 AC: 2314 AN: 68010

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0292 Hom.: 247

Bravo AF: 0.0245

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0325

EpiControl AF: 0.0338

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cone-rod dystrophy 7 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.029	D
Varity_R		0.30
gMVP		0.65
Mutation Taster		=45/55	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41265501;

hg19: chr6-72984123;

COSMIC: COSV53450187;