rs11078398

Positions:

• chr17-17793785-G-A
• chr17-17793785-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030665.4(RAI1):​c.837G>A​(p.Gln279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0080 (32 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.45

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-17793785-G-A is Benign according to our data. Variant chr17-17793785-G-A is described in ClinVar as [Benign]. Clinvar id is 96198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793785-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.837G>A	p.Gln279=	synonymous_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.837G>A	p.Gln279=	synonymous_variant	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.837G>A	p.Gln279=	synonymous_variant	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 287 AN: 54134 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00558

Gnomad ASJ AF: 0.00239

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.000254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00674

GnomAD3 exomes AF: 0.0489 AC: 9588 AN: 195896 Hom.: 2486 AF XY: 0.0451 AC XY: 4863 AN XY: 107906

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.0812

Gnomad SAS exome AF: 0.0610

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0375

Gnomad OTH exome AF: 0.0390

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00796 AC: 4154 AN: 522176 Hom.: 32 Cov.: 0 AF XY: 0.00944 AC XY: 2402 AN XY: 254516

Gnomad4 AFR exome AF: 0.00315

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.00882

Gnomad4 NFE exome AF: 0.00389

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.00532 AC: 288 AN: 54172 Hom.: 5 Cov.: 0 AF XY: 0.00601 AC XY: 154 AN XY: 25640

Gnomad4 AFR AF: 0.00252

Gnomad4 AMR AF: 0.00557

Gnomad4 ASJ AF: 0.00239

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.000254

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.202 Hom.: 855

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

RAI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2022

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
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.90
DANN	Benign	0.39

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: rs11078398; hg19: chr17-17697099; COSMIC: COSV55388938; COSMIC: COSV55388938;