NM_014989.7:c.648G>A

Variant names:

• chr6-72179751-G-A
• rs116303981
• NM_014989.7:c.648G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014989.7(RIMS1):​c.648G>A​(p.Ser216Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,804 control chromosomes in the GnomAD database, including 25 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. S216S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0077 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (10 hom.)
• Consequence: RIMS1 NM_014989.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.24
• Publications: 1 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, 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-72179751-G-A is Benign according to our data. Variant chr6-72179751-G-A is described in ClinVar as Benign. ClinVar VariationId is 260499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00765 (1165/152196) while in subpopulation AFR AF = 0.026 (1080/41532). AF 95% confidence interval is 0.0247. There are 15 homozygotes in GnomAd4. There are 564 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1165 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.648G>A	p.Ser216Ser	synonymous	Exon 5 of 34	NP_055804.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.648G>A	p.Ser216Ser	synonymous	Exon 5 of 34	ENSP00000428417.1	Q86UR5-1
	RIMS1	ENST00000264839.11	TSL:5	c.648G>A	p.Ser216Ser	synonymous	Exon 5 of 30	ENSP00000264839.7	Q86UR5-4
	RIMS1	ENST00000697193.1		c.648G>A	p.Ser216Ser	synonymous	Exon 5 of 29	ENSP00000513179.1	A0A8V8TKU9

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1160 AN: 152078 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00194 AC: 483 AN: 248762 AF XY: 0.00141

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000776 AC: 1134 AN: 1461608 Hom.: 10 Cov.: 30 AF XY: 0.000653 AC XY: 475 AN XY: 727064

African (AFR) AF: 0.0248 AC: 831 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53302

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111868

Other (OTH) AF: 0.00202 AC: 122 AN: 60372

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152196 Hom.: 15 Cov.: 32 AF XY: 0.00758 AC XY: 564 AN XY: 74422

African (AFR) AF: 0.0260 AC: 1080 AN: 41532

American (AMR) AF: 0.00392 AC: 60 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00303 Hom.: 5

Bravo AF: 0.00923

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.40
DANN	Benign	0.57
PhyloP100		-3.2
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116303981; hg19: chr6-72889454;