rs1582803774

Variant names:

• chr6-71887064-C-T
• rs1582803774
• NM_014989.7:c.41C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014989.7(RIMS1):​c.41C>T​(p.Thr14Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIMS1 NM_014989.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28413442).

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.41C>T	p.Thr14Met	missense	Exon 1 of 34	NP_055804.2
	RIMS1	NM_001350413.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 4	NP_001337342.1
	RIMS1	NM_001350411.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 4	NP_001337340.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.41C>T	p.Thr14Met	missense	Exon 1 of 34	ENSP00000428417.1	Q86UR5-1
	RIMS1	ENST00000264839.11	TSL:5	c.41C>T	p.Thr14Met	missense	Exon 1 of 30	ENSP00000264839.7	Q86UR5-4
	RIMS1	ENST00000697193.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 29	ENSP00000513179.1	A0A8V8TKU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461158 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726824

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111678

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.071
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.14		Loss of phosphorylation at T14 (P = 0.0015)
MVP		0.66
MPC		1.6
ClinPred		0.91	D
GERP RS		4.6
PromoterAI		0.0066	Neutral
Varity_R		0.27
gMVP		0.59
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1582803774; hg19: chr6-72596767; COSMIC: COSV99328440;