rs398124417

Positions:

chr17-17796723-AAGG-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.3781_3783delGAG(p.Glu1261del) variant causes a conservative 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 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 7.59

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	3/6	ENST00000353383.6	NP_109590.3	Q7Z5J4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 linkuse as main transcript	c.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	3/6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152106

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00279

AC XY:

378

AN XY:

135576

show subpopulations

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.:

AF XY:

0.00490

AC XY:

3559

AN XY:

726860

show subpopulations

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.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.00363

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

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	Jan 08, 2019	This variant is associated with the following publications: (PMID: 21857958) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	RAI1: PM4:Supporting, BS1, BS2 -

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

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
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	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, no assertion criteria provided

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over