11-66332290-C-T

Variant names:

• chr11-66332290-C-T
• rs751629204
• NM_004292.3:c.2338G>A

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.2338G>A​(p.Ala780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,688 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RIN1 NM_004292.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.277
• 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=0.058505535).

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.2338G>A	p.Ala780Thr	missense	Exon 10 of 10	NP_004283.2	A0A0S2Z4U0
	RIN1	NM_001363559.2		c.2254G>A	p.Ala752Thr	missense	Exon 10 of 10	NP_001350488.1
	RIN1	NM_001363560.2		c.2152G>A	p.Ala718Thr	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.2338G>A	p.Ala780Thr	missense	Exon 10 of 10	ENSP00000310406.4	Q13671-1
	RIN1	ENST00000970357.1		c.2185G>A	p.Ala729Thr	missense	Exon 10 of 10	ENSP00000640416.1
	RIN1	ENST00000869551.1		c.2152G>A	p.Ala718Thr	missense	Exon 10 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251410 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461688 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.28
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.047
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.040	D
Polyphen		0.0080	B
Vest4		0.065
MutPred		0.17		Gain of phosphorylation at A780 (P = 0.005)
MVP		0.22
MPC		0.37
ClinPred		0.094	T
GERP RS		2.3
Varity_R		0.025
gMVP		0.12
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: rs751629204; hg19: chr11-66099761;