17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAG

Position:

• chr17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.855_872del​(p.Gln286_Gln291del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000876 in 1,357,732 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: RAI1 NM_030665.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:3
• 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-CCAGCAGCAGCAGCAGCAG-C is Benign according to our data. Variant chr17-17793779-CCAGCAGCAGCAGCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 588724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793779-CCAGCAGCAGCAGCAGCAG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000127 (10/78922) while in subpopulation SAS AF= 0.00244 (2/818). AF 95% confidence interval is 0.000433. There are 1 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.855_872del	p.Gln286_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.855_872del	p.Gln286_Gln291del	inframe_deletion	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.855_872del	p.Gln286_Gln291del	inframe_deletion	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 10 AN: 78832 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000158

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 109 AN: 1278810 Hom.: 0 AF XY: 0.0000822 AC XY: 52 AN XY: 632488

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.000126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000537

Gnomad4 SAS exome AF: 0.0000896

Gnomad4 FIN exome AF: 0.0000217

Gnomad4 NFE exome AF: 0.0000796

Gnomad4 OTH exome AF: 0.000231

GnomAD4 genome AF: 0.000127 AC: 10 AN: 78922 Hom.: 1 Cov.: 0 AF XY: 0.000133 AC XY: 5 AN XY: 37510

Gnomad4 AFR AF: 0.0000420

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00134

Gnomad4 SAS AF: 0.00244

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000158

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAI1 p.Gln286_Gln291del variant was not identified in the literature nor was it identified in dbSNP, Cosmic or LOVD 3.0. The variant was identified in ClinVar (classified as likely benign by Ambry Genetics). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a glutamine (gln) residue from codons 286-291; the impact of this alteration on RAI1 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2017

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

This variant is classified as likely 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

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;