rs398124417

Positions:

• chr17-17796723-AAGG-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.3781_3783del​(p.Glu1261del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,613,430 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (32 hom.)
• Consequence: RAI1 NM_030665.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.59

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_030665.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-17796723-AAGG-A is Benign according to our data. Variant chr17-17796723-AAGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 96187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17796723-AAGG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00371 (564/152224) while in subpopulation NFE AF= 0.00542 (369/68024). AF 95% confidence interval is 0.00497. There are 7 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.3781_3783del	p.Glu1261del	inframe_deletion	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.3781_3783del	p.Glu1261del	inframe_deletion	3/6	1	NM_030665.4	P1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152106 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00278 AC: 696 AN: 250626 Hom.: 2 AF XY: 0.00279 AC XY: 378 AN XY: 135576

Gnomad AFR exome AF: 0.000990

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00499 AC: 7288 AN: 1461206 Hom.: 32 AF XY: 0.00490 AC XY: 3559 AN XY: 726860

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00351

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00371 AC: 564 AN: 152224 Hom.: 7 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74422

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00542

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00363

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	This variant is associated with the following publications: (PMID: 21857958) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RAI1: PM4:Supporting, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAI1 p.Glu1261del variant was identified in the literature in a patient with Smith-Magenis syndrome, however the variant was also present in her unaffected father (Vilboux_2011_PMID:21857958). The variant was identified in dbSNP (ID: rs149716029) and ClinVar (classified as benign by Genetic Services Laboratory, University of Chicago and EGL Diagnostics, as likely benign by Prevention Genetics, Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, GeneDx and Ambry Genetics, and uncertain significance by Genetic Services Laboratory, University of Chicago). The variant was identified in control databases in 794 of 281978 chromosomes (2 homozygous) at a frequency of 0.002816 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 630 of 128542 chromosomes (freq: 0.004901), Other in 23 of 7200 chromosomes (freq: 0.003194), European (Finnish) in 73 of 25096 chromosomes (freq: 0.002909), Latino in 43 of 35404 chromosomes (freq: 0.001215), African in 23 of 24850 chromosomes (freq: 0.000926), Ashkenazi Jewish in 1 of 10344 chromosomes (freq: 0.000097) and South Asian in 1 of 30610 chromosomes (freq: 0.000033), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codon 1261; the impact of this alteration on RAI1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Smith-Magenis syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 31, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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. -

RAI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2020

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). -

Computational scores

Source: dbNSFP v4.3

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: rs149716029; hg19: chr17-17700037;