11-66332355-C-G

Variant names:

• chr11-66332355-C-G
• rs765691604
• NM_004292.3:c.2273G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004292.3(RIN1):​c.2273G>C​(p.Gly758Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G758V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIN1 NM_004292.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.342
• Publications: 0 publications found

Genes affected

RIN1 (HGNC:18749): (Ras and Rab interactor 1) Predicted to enable small GTPase binding activity. Predicted to be involved in endocytosis; regulation of catalytic activity; and signal transduction. Predicted to act upstream of or within associative learning; memory; and negative regulation of synaptic plasticity. Located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RIN1 Gene-Disease associations (from GenCC):

• familial nonmedullary thyroid carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000254756 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05528918).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004292.3. 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
	RIN1	NM_004292.3	MANE Select	c.2273G>C	p.Gly758Ala	missense	Exon 10 of 10	NP_004283.2	A0A0S2Z4U0
	RIN1	NM_001363559.2		c.2189G>C	p.Gly730Ala	missense	Exon 10 of 10	NP_001350488.1
	RIN1	NM_001363560.2		c.2087G>C	p.Gly696Ala	missense	Exon 10 of 10	NP_001350489.1	Q13671-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN1	ENST00000311320.9	TSL:1 MANE Select	c.2273G>C	p.Gly758Ala	missense	Exon 10 of 10	ENSP00000310406.4	Q13671-1
	RIN1	ENST00000970357.1		c.2120G>C	p.Gly707Ala	missense	Exon 10 of 10	ENSP00000640416.1
	RIN1	ENST00000869551.1		c.2087G>C	p.Gly696Ala	missense	Exon 10 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.34
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.020
Sift	Benign	0.050	D
Sift4G	Benign	0.15	T
Polyphen		0.043	B
Vest4		0.12
MutPred		0.12		Gain of helix (P = 0.0078)
MVP		0.28
MPC		0.19
ClinPred		0.11	T
GERP RS		-0.71
Varity_R		0.031
gMVP		0.17
Mutation Taster		=97/3	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: rs765691604; hg19: chr11-66099826;