chr17-17793787-AG-A

Position:

• chr17-17793787-AG-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_030665.4(RAI1):​c.840del​(p.Gln280HisfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q280Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.38 (11070 hom., cov: 0)
  • Exomes 𝑓: 0.33 (48739 hom.)
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.466

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 -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 17-17793787-AG-A is Benign according to our data. Variant chr17-17793787-AG-A is described in ClinVar as [Benign]. Clinvar id is 587783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793787-AG-A is described in Lovd as [Benign]. Variant chr17-17793787-AG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.840del	p.Gln280HisfsTer84	frameshift_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.840del	p.Gln280HisfsTer84	frameshift_variant	3/6	1	NM_030665.4	P1
RAI1	ENST00000395774.1	c.840del	p.Gln280HisfsTer84	frameshift_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 54845 AN: 145638 Hom.: 11075 Cov.: 0

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.237 AC: 42962 AN: 181254 Hom.: 12205 AF XY: 0.241 AC XY: 23997 AN XY: 99682

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.585

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.326 AC: 445687 AN: 1368702 Hom.: 48739 Cov.: 0 AF XY: 0.332 AC XY: 226114 AN XY: 681328

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.490

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.552

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.350

GnomAD4 genome AF: 0.376 AC: 54861 AN: 145752 Hom.: 11070 Cov.: 0 AF XY: 0.389 AC XY: 27738 AN XY: 71326

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.843

Gnomad4 SAS AF: 0.701

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.379

Alfa AF: 0.00191 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2017

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

Mendelics

May 28, 2019

- -

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: rs34083643; hg19: chr17-17697101; COSMIC: COSV55389171; COSMIC: COSV55389171;