chr6-72392740-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014989.7(RIMS1):​c.4548C>A​(p.Phe1516Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1516F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIMS1 NM_014989.7 missense
• Clinical Significance: Not reported in ClinVar
• 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, Ambry Genetics, Illumina, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMS1	NM_014989.7	c.4548C>A	p.Phe1516Leu	missense_variant	Exon 31 of 34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6	c.4548C>A	p.Phe1516Leu	missense_variant	Exon 31 of 34	1	NM_014989.7	ENSP00000428417.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;.;.;D;.;.;.;.;.;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.;.;.;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.97	.;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.64
MutPred		0.26		.;.;.;.;Gain of disorder (P = 0.1255);.;.;.;.;.;.;.;.;.;
MVP		0.53
MPC		1.8
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.59
gMVP		0.49
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;