NM_004292.3:c.1772G>A

Variant names:

• chr11-66333361-C-T
• rs375956582
• NM_004292.3:c.1772G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004292.3(RIN1):​c.1772G>A​(p.Gly591Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,612,594 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: RIN1 NM_004292.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.485
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008468151).
• BS2: High AC in GnomAd4 at 28 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.1772G>A	p.Gly591Asp	missense	Exon 9 of 10	NP_004283.2	A0A0S2Z4U0
	RIN1	NM_001363559.2		c.1688G>A	p.Gly563Asp	missense	Exon 9 of 10	NP_001350488.1
	RIN1	NM_001363560.2		c.1586G>A	p.Gly529Asp	missense	Exon 9 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.1772G>A	p.Gly591Asp	missense	Exon 9 of 10	ENSP00000310406.4	Q13671-1
	RIN1	ENST00000970357.1		c.1619G>A	p.Gly540Asp	missense	Exon 9 of 10	ENSP00000640416.1
	RIN1	ENST00000869551.1		c.1586G>A	p.Gly529Asp	missense	Exon 9 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000379 AC: 94 AN: 248346 AF XY: 0.000342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00837

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000805

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1460402 Hom.: 1 Cov.: 33 AF XY: 0.000195 AC XY: 142 AN XY: 726466

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00764 AC: 199 AN: 26060

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111484

Other (OTH) AF: 0.000613 AC: 37 AN: 60332

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41452

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

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000703 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.48
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.069
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.33
MVP		0.25
MPC		0.27
ClinPred		0.041	T
GERP RS		4.0
Varity_R		0.074
gMVP		0.22
Mutation Taster		=84/16	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: rs375956582; hg19: chr11-66100832;