6-72392740-C-T

Variant names:

• chr6-72392740-C-T
• rs2815738
• NM_014989.7:c.4548C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014989.7(RIMS1):​c.4548C>T​(p.Phe1516Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,611,926 control chromosomes in the GnomAD database, including 43,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3362 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40117 hom.)
• Consequence: RIMS1 NM_014989.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BP6: Variant 6-72392740-C-T is Benign according to our data. Variant chr6-72392740-C-T is described in ClinVar as Benign. ClinVar VariationId is 260498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

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.4548C>T	p.Phe1516Phe	synonymous	Exon 31 of 34	NP_055804.2
	RIMS1	NM_001350436.2		c.2700C>T	p.Phe900Phe	synonymous	Exon 24 of 27	NP_001337365.1
	RIMS1	NM_001350446.2		c.2694C>T	p.Phe898Phe	synonymous	Exon 23 of 26	NP_001337375.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.4548C>T	p.Phe1516Phe	synonymous	Exon 31 of 34	ENSP00000428417.1	Q86UR5-1
	RIMS1	ENST00000425662.6	TSL:1	c.1752C>T	p.Phe584Phe	synonymous	Exon 19 of 22	ENSP00000411235.2	Q86UR5-10
	RIMS1	ENST00000370420.8	TSL:1	c.1692C>T	p.Phe564Phe	synonymous	Exon 14 of 17	ENSP00000359448.4	A0A0C4DFV1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30524 AN: 151870 Hom.: 3360 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.209 AC: 52052 AN: 249168 AF XY: 0.220

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0160

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.228 AC: 332575 AN: 1459938 Hom.: 40117 Cov.: 32 AF XY: 0.231 AC XY: 167619 AN XY: 726374

African (AFR) AF: 0.153 AC: 5131 AN: 33454

American (AMR) AF: 0.110 AC: 4905 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 7046 AN: 26118

East Asian (EAS) AF: 0.0168 AC: 666 AN: 39678

South Asian (SAS) AF: 0.297 AC: 25612 AN: 86186

European-Finnish (FIN) AF: 0.257 AC: 13719 AN: 53390

Middle Eastern (MID) AF: 0.270 AC: 1554 AN: 5764

European-Non Finnish (NFE) AF: 0.235 AC: 260902 AN: 1110324

Other (OTH) AF: 0.216 AC: 13040 AN: 60310

GnomAD4 genome AF: 0.201 AC: 30556 AN: 151988 Hom.: 3362 Cov.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74290

African (AFR) AF: 0.158 AC: 6554 AN: 41438

American (AMR) AF: 0.148 AC: 2261 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 934 AN: 3466

East Asian (EAS) AF: 0.0177 AC: 92 AN: 5184

South Asian (SAS) AF: 0.293 AC: 1410 AN: 4818

European-Finnish (FIN) AF: 0.258 AC: 2719 AN: 10528

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15882 AN: 67980

Other (OTH) AF: 0.209 AC: 441 AN: 2110

Alfa AF: 0.222 Hom.: 6532

Bravo AF: 0.189

Asia WGS AF: 0.153 AC: 535 AN: 3478

EpiCase AF: 0.245

EpiControl AF: 0.241

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		1.4
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2815738; hg19: chr6-73102442; COSMIC: COSV108068682;