rs11227461

Variant names:

• chr11-66332530-C-G
• rs11227461
• NM_004292.3:c.2098G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-66332530-C-G
• chr11-66332530-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004292.3(RIN1):​c.2098G>C​(p.Val700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V700I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RIN1 NM_004292.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 6 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13265201).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

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.2098G>C	p.Val700Leu	missense	Exon 10 of 10	NP_004283.2	A0A0S2Z4U0
	RIN1	NM_001363559.2		c.2014G>C	p.Val672Leu	missense	Exon 10 of 10	NP_001350488.1
	RIN1	NM_001363560.2		c.1912G>C	p.Val638Leu	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.2098G>C	p.Val700Leu	missense	Exon 10 of 10	ENSP00000310406.4	Q13671-1
	RIN1	ENST00000970357.1		c.1945G>C	p.Val649Leu	missense	Exon 10 of 10	ENSP00000640416.1
	RIN1	ENST00000869551.1		c.1912G>C	p.Val638Leu	missense	Exon 10 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461236 Hom.: 0 Cov.: 69 AF XY: 0.00000688 AC XY: 5 AN XY: 726910

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

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111626

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.37
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.036
Sift	Benign	0.30	T
Sift4G	Uncertain	0.050	T
Polyphen		0.45	B
Vest4		0.20
MutPred		0.51		Loss of sheet (P = 0.0228)
MVP		0.14
MPC		0.44
ClinPred		0.093	T
GERP RS		0.77
Varity_R		0.059
gMVP		0.46
Mutation Taster		=98/2	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: rs11227461; hg19: chr11-66100001;