chr11-66332530-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004292.3(RIN1):​c.2098G>A​(p.Val700Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,596 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (7 hom., cov: 34)
  • Exomes 𝑓: 0.00084 (12 hom.)
• Consequence: RIN1 NM_004292.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071160793).
• BP6: Variant 11-66332530-C-T is Benign according to our data. Variant chr11-66332530-C-T is described in ClinVar as Benign. ClinVar VariationId is 785362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 539 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>A	p.Val700Ile	missense	Exon 10 of 10	NP_004283.2	A0A0S2Z4U0
	RIN1	NM_001363559.2		c.2014G>A	p.Val672Ile	missense	Exon 10 of 10	NP_001350488.1
	RIN1	NM_001363560.2		c.1912G>A	p.Val638Ile	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>A	p.Val700Ile	missense	Exon 10 of 10	ENSP00000310406.4	Q13671-1
	RIN1	ENST00000970357.1		c.1945G>A	p.Val649Ile	missense	Exon 10 of 10	ENSP00000640416.1
	RIN1	ENST00000869551.1		c.1912G>A	p.Val638Ile	missense	Exon 10 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 535 AN: 152242 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 250318 AF XY: 0.00160

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000836 AC: 1221 AN: 1461236 Hom.: 12 Cov.: 69 AF XY: 0.000962 AC XY: 699 AN XY: 726910

African (AFR) AF: 0.0131 AC: 438 AN: 33480

American (AMR) AF: 0.000716 AC: 32 AN: 44708

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00573 AC: 494 AN: 86218

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

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111626

Other (OTH) AF: 0.00192 AC: 116 AN: 60370

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152360 Hom.: 7 Cov.: 34 AF XY: 0.00340 AC XY: 253 AN XY: 74500

African (AFR) AF: 0.0114 AC: 475 AN: 41582

American (AMR) AF: 0.00157 AC: 24 AN: 15304

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

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000821 Hom.: 1

Bravo AF: 0.00365

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.37
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.016
Sift	Benign	0.37	T
Sift4G	Benign	0.57	T
Polyphen		0.027	B
Vest4		0.097
MVP		0.081
MPC		0.16
ClinPred		0.0014	T
GERP RS		0.77
Varity_R		0.024
gMVP		0.18
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; COSMIC: COSV60925988; COSMIC: COSV60925988;