rs35686634

chr17-17797478-C-T

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.4530C>T(p.Pro1510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,613,206 control chromosomes in the GnomAD database, including 3,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (892 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2985 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.392

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=-0.85).
• BP6: Variant 17-17797478-C-T is Benign according to our data. Variant chr17-17797478-C-T is described in ClinVar as [Benign]. Clinvar id is 96192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17797478-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.4530C>T	p.Pro1510=	synonymous_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.4530C>T	p.Pro1510=	synonymous_variant	3/6	1	NM_030665.4	P1

Frequencies

GnomAD3 genomes AF: 0.0884 AC: 13439 AN: 152096 Hom.: 886 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0553 AC: 13767 AN: 249068 Hom.: 640 AF XY: 0.0530 AC XY: 7168 AN XY: 135294

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00290

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.0781

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0532

GnomAD4 exome AF: 0.0584 AC: 85385 AN: 1460992 Hom.: 2985 Cov.: 37 AF XY: 0.0568 AC XY: 41269 AN XY: 726794

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.0342

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0268

Gnomad4 FIN exome AF: 0.0763

Gnomad4 NFE exome AF: 0.0600

Gnomad4 OTH exome AF: 0.0596

GnomAD4 genome AF: 0.0886 AC: 13483 AN: 152214 Hom.: 892 Cov.: 33 AF XY: 0.0878 AC XY: 6532 AN XY: 74436

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0454

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0587

Gnomad4 OTH AF: 0.0833

Alfa AF: 0.0697 Hom.: 255

Bravo AF: 0.0906

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Dec 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 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. -

Smith-Magenis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.78
Dann	Benign	0.35

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: rs35686634; hg19: chr17-17700792;