rs150563155

chr17-17793673-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):c.725C>T(p.Pro242Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,134 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P242S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.61

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004776269).
• BP6: Variant 17-17793673-C-T is Benign according to our data. Variant chr17-17793673-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793673-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00235 (358/152274) while in subpopulation SAS AF= 0.00435 (21/4830). AF 95% confidence interval is 0.00325. There are 0 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4	c.725C>T	p.Pro242Leu	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6	c.725C>T	p.Pro242Leu	missense_variant	3/6	1	NM_030665.4	P1
RAI1	ENST00000395774.1	c.725C>T	p.Pro242Leu	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00298 AC: 738 AN: 247306 Hom.: 2 AF XY: 0.00347 AC XY: 467 AN XY: 134608

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00422

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00874

GnomAD4 exome AF: 0.00214 AC: 3127 AN: 1460860 Hom.: 11 Cov.: 97 AF XY: 0.00233 AC XY: 1690 AN XY: 726736

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00423

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74460

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00340 Hom.: 2

Bravo AF: 0.00280

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00338 AC: 29

ExAC AF: 0.00286 AC: 347

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 21857958, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RAI1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 18, 2021

- -

RAI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2021

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
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	0.038
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.74
MVP		0.19
MPC		0.94
ClinPred		0.024	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150563155; hg19: chr17-17696987; COSMIC: COSV99062882; COSMIC: COSV99062882;