rs3818717

Positions:

• chr17-17803791-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030665.4(RAI1):​c.5601T>C​(p.Ile1867=) 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

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• 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. Variant chr17-17803791-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
RAI1	NM_030665.4	c.5601T>C	p.Ile1867=	synonymous_variant	4/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.5601T>C	p.Ile1867=	synonymous_variant	4/6	1	NM_030665.4	P1
RAI1	ENST00000583166.1	c.168T>C	p.Ile56=	synonymous_variant	2/2	2

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

GnomAD3 exomes AF: 0.423 AC: 106132 AN: 250822 Hom.: 26408 AF XY: 0.425 AC XY: 57689 AN XY: 135794

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 SAS exome AF: 0.210

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

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.0778

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.485

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

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.0772

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.431

Alfa AF: 0.528 Hom.: 27737

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Smith-Magenis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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