rs3818717

Variant names:

• chr17-17803791-T-C
• rs3818717
• NM_030665.4:c.5601T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_030665.4(RAI1):​c.5601T>C​(p.Ile1867Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,612,858 control chromosomes in the GnomAD database, including 229,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15623 hom., cov: 33)
  • Exomes 𝑓: 0.52 (214154 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.76
• Publications: 42 publications found

Genes affected

RAI1 (HGNC:9834): (retinoic acid induced 1) This gene is located within the Smith-Magenis syndrome region on chromosome 17. It is highly similar to its mouse counterpart and is expressed at high levels mainly in neuronal tissues. The protein encoded by this gene includes a polymorphic polyglutamine tract in the N-terminal domain. Expression of the mouse counterpart in neurons is induced by retinoic acid. This gene is associated with both the severity of the phenotype and the response to medication in schizophrenic patients. [provided by RefSeq, Jul 2008]

RAI1 Gene-Disease associations (from GenCC):

• Smith-Magenis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Potocki-Lupski syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 17-17803791-T-C is Benign according to our data. Variant chr17-17803791-T-C is described in ClinVar as [Benign]. Clinvar id is 96195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4	c.5601T>C	p.Ile1867Ile	synonymous_variant	Exon 4 of 6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.5601T>C	p.Ile1867Ile	synonymous_variant	Exon 4 of 6	1	NM_030665.4	ENSP00000323074.4
RAI1	ENST00000583166.1	c.165T>C	p.Ile55Ile	synonymous_variant	Exon 2 of 2	2		ENSP00000463984.1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63339 AN: 152034 Hom.: 15622 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.433

GnomAD2 exomes AF: 0.423 AC: 106132 AN: 250822 AF XY: 0.425

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.0747

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.523 AC: 764604 AN: 1460706 Hom.: 214154 Cov.: 51 AF XY: 0.516 AC XY: 374683 AN XY: 726666

African (AFR) AF: 0.178 AC: 5951 AN: 33470

American (AMR) AF: 0.336 AC: 15026 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 13891 AN: 26132

East Asian (EAS) AF: 0.0778 AC: 3088 AN: 39698

South Asian (SAS) AF: 0.215 AC: 18549 AN: 86252

European-Finnish (FIN) AF: 0.528 AC: 27780 AN: 52652

Middle Eastern (MID) AF: 0.460 AC: 2655 AN: 5766

European-Non Finnish (NFE) AF: 0.583 AC: 648365 AN: 1111650

Other (OTH) AF: 0.485 AC: 29299 AN: 60370

GnomAD4 genome AF: 0.416 AC: 63350 AN: 152152 Hom.: 15623 Cov.: 33 AF XY: 0.407 AC XY: 30254 AN XY: 74398

African (AFR) AF: 0.196 AC: 8121 AN: 41518

American (AMR) AF: 0.391 AC: 5973 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1838 AN: 3470

East Asian (EAS) AF: 0.0772 AC: 400 AN: 5180

South Asian (SAS) AF: 0.208 AC: 1003 AN: 4828

European-Finnish (FIN) AF: 0.513 AC: 5431 AN: 10584

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 39042 AN: 67974

Other (OTH) AF: 0.431 AC: 910 AN: 2112

Alfa AF: 0.516 Hom.: 33053

Bravo AF: 0.399

Asia WGS AF: 0.176 AC: 613 AN: 3478

EpiCase AF: 0.557

EpiControl AF: 0.556

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Smith-Magenis syndrome Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs3818717; hg19: chr17-17707105; COSMIC: COSV55393781;