17-17793787-AGCAG-A

Position:

• chr17-17793787-AGCAG-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.840_843del​(p.Gln280HisfsTer83) 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 Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00092 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.03

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-AGCAG-A is Benign according to our data. Variant chr17-17793787-AGCAG-A is described in ClinVar as [Benign]. Clinvar id is 403362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793787-AGCAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000961 (140/145748) while in subpopulation EAS AF= 0.00337 (17/5048). AF 95% confidence interval is 0.00215. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.840_843del	p.Gln280HisfsTer83	frameshift_variant	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.840_843del	p.Gln280HisfsTer83	frameshift_variant	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.840_843del	p.Gln280HisfsTer83	frameshift_variant	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 140 AN: 145634 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000887

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000547

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00336

Gnomad SAS AF: 0.00251

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000510

GnomAD3 exomes AF: 0.0393 AC: 7127 AN: 181254 Hom.: 653 AF XY: 0.0394 AC XY: 3925 AN XY: 99682

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.0816

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0378

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000919 AC: 1176 AN: 1279016 Hom.: 6 AF XY: 0.00100 AC XY: 633 AN XY: 631838

Gnomad4 AFR exome AF: 0.000826

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.0000915

Gnomad4 EAS exome AF: 0.00620

Gnomad4 SAS exome AF: 0.00523

Gnomad4 FIN exome AF: 0.00725

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.000996

GnomAD4 genome AF: 0.000961 AC: 140 AN: 145748 Hom.: 1 Cov.: 0 AF XY: 0.00108 AC XY: 77 AN XY: 71318

Gnomad4 AFR AF: 0.000884

Gnomad4 AMR AF: 0.000546

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00337

Gnomad4 SAS AF: 0.00251

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000504

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: VQSRTrancheINDEL97.00to99.00 (11.52% South Asian) -

not provided Benign:2

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	GeneDx	Aug 06, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

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

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

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: rs775735568; hg19: chr17-17697101;