rs150563155

Positions:

chr17-17793673-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 11 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.61

Variant links:

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]

RAI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.725C>T	p.Pro242Leu	missense_variant	3/6	ENST00000353383.6	NP_109590.3	Q7Z5J4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 linkuse as main transcript	c.725C>T	p.Pro242Leu	missense_variant	3/6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 linkuse as main transcript	c.725C>T	p.Pro242Leu	missense_variant	2/2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00347

AC XY:

467

AN XY:

134608

show subpopulations

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.:

Cov.:

AF XY:

0.00233

AC XY:

1690

AN XY:

726736

show subpopulations

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.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74460

show subpopulations

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.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00338

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:9

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 21857958, 27884173) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RAI1: BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2019	- -

not specified

Benign:2

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

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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;.

Eigen

Benign

0.038

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.58

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over