17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAG

Position:

• chr17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_030665.4(RAI1):​c.861_872del​(p.Gln288_Gln291del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0341 in 1,357,426 control chromosomes in the GnomAD database, including 321 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (71 hom., cov: 0)
  • Exomes 𝑓: 0.033 (250 hom.)
• Consequence: RAI1 NM_030665.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.86

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 -16 ACMG points.

• BP6: Variant 17-17793779-CCAGCAGCAGCAG-C is Benign according to our data. Variant chr17-17793779-CCAGCAGCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 130088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793779-CCAGCAGCAGCAG-C is described in Lovd as [Benign]. Variant chr17-17793779-CCAGCAGCAGCAG-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.861_872del	p.Gln288_Gln291del	inframe_deletion	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.861_872del	p.Gln288_Gln291del	inframe_deletion	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.861_872del	p.Gln288_Gln291del	inframe_deletion	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 3854 AN: 78814 Hom.: 70 Cov.: 0

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0684

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.00267

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0621

GnomAD4 exome AF: 0.0332 AC: 42400 AN: 1278522 Hom.: 250 AF XY: 0.0331 AC XY: 20932 AN XY: 632354

Gnomad4 AFR exome AF: 0.00626

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.0787

Gnomad4 EAS exome AF: 0.000379

Gnomad4 SAS exome AF: 0.00495

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0346

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0488 AC: 3854 AN: 78904 Hom.: 71 Cov.: 0 AF XY: 0.0469 AC XY: 1760 AN XY: 37504

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.00267

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0681

Gnomad4 NFE AF: 0.0613

Gnomad4 OTH AF: 0.0611

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2016

This alteration is classified as likely 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. -

RAI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2017

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other strong data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371983878; hg19: chr17-17697093;