rs35068024

Positions:

• chr17-17793784-AGC-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.837_838del​(p.Gln280AlafsTer108) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,455,922 control chromosomes in the GnomAD database, including 113,580 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.39 (11743 hom., cov: 0)
  • Exomes 𝑓: 0.39 (101837 hom.)
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.64

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 17-17793784-AGC-A is Benign according to our data. Variant chr17-17793784-AGC-A is described in ClinVar as [Benign]. Clinvar id is 167555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793784-AGC-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.837_838del	p.Gln280AlafsTer108	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.837_838del	p.Gln280AlafsTer108	frameshift_variant	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.837_838del	p.Gln280AlafsTer108	frameshift_variant	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.394 AC: 56570 AN: 143594 Hom.: 11744 Cov.: 0

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.393

GnomAD3 exomes AF: 0.379 AC: 75378 AN: 198702 Hom.: 22472 AF XY: 0.384 AC XY: 42252 AN XY: 110070

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.741

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.387 AC: 507253 AN: 1312242 Hom.: 101837 AF XY: 0.396 AC XY: 259412 AN XY: 654896

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.594

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.844

Gnomad4 SAS exome AF: 0.703

Gnomad4 FIN exome AF: 0.377

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.394 AC: 56593 AN: 143680 Hom.: 11743 Cov.: 0 AF XY: 0.406 AC XY: 28581 AN XY: 70372

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.851

Gnomad4 SAS AF: 0.707

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.391

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2014	- -
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: Frequency in 1000Genomes: 272/2178=12.4% -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

This variant is associated with the following publications: (PMID: 27884173, 23585368) -

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: rs35068024; hg19: chr17-17697098; COSMIC: COSV55394436; COSMIC: COSV55394436;