rs11649804

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030665.4(RAI1):c.493C>A(p.Pro165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,504 control chromosomes in the GnomAD database, including 115,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P165R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 11981 hom., cov: 32)

Exomes 𝑓: 0.35 ( 103887 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.710

Publications

63 publications found

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 Gene-Disease associations (from GenCC):

Smith-Magenis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Potocki-Lupski syndrome
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RAI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.54322E-7).

BP6

Variant 17-17793441-C-A is Benign according to our data. Variant chr17-17793441-C-A is described in ClinVar as Benign. ClinVar VariationId is 96194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.493C>A	p.Pro165Thr	missense_variant	Exon 3 of 6	ENST00000353383.6	NP_109590.3	Q7Z5J4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 link	c.493C>A	p.Pro165Thr	missense_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.493C>A	p.Pro165Thr	missense_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57083

AN:

151868

Hom.:

11979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.845

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.366

GnomAD2 exomes

AF:

0.443

AC:

111013

AN:

250752

AF XY:

0.447

show subpopulations

Gnomad AFR exome

AF:

0.393

Gnomad AMR exome

AF:

0.583

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.852

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.350

AC:

511481

AN:

1461518

Hom.:

103887

Cov.:

AF XY:

0.360

AC XY:

261888

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.395

AC:

13237

AN:

33480

American (AMR)

AF:

0.569

AC:

25458

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

8629

AN:

26134

East Asian (EAS)

AF:

0.832

AC:

33020

AN:

39700

South Asian (SAS)

AF:

0.713

AC:

61524

AN:

86256

European-Finnish (FIN)

AF:

0.321

AC:

17060

AN:

53068

Middle Eastern (MID)

AF:

0.392

AC:

2256

AN:

5762

European-Non Finnish (NFE)

AF:

0.295

AC:

327681

AN:

1112000

Other (OTH)

AF:

0.374

AC:

22616

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

22982

45964

68945

91927

114909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11220

22440

33660

44880

56100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.376

AC:

57111

AN:

151986

Hom.:

11981

Cov.:

AF XY:

0.388

AC XY:

28833

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.381

AC:

15797

AN:

41430

American (AMR)

AF:

0.466

AC:

7126

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1114

AN:

3468

East Asian (EAS)

AF:

0.845

AC:

4370

AN:

5170

South Asian (SAS)

AF:

0.724

AC:

3488

AN:

4818

European-Finnish (FIN)

AF:

0.333

AC:

3520

AN:

10572

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.301

AC:

20480

AN:

67934

Other (OTH)

AF:

0.364

AC:

768

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1736

3472

5207

6943

8679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.335

Hom.:

40271

Bravo

AF:

0.383

TwinsUK

AF:

0.287

AC:

1064

ALSPAC

AF:

0.297

AC:

1144

ESP6500AA

AF:

0.395

AC:

1742

ESP6500EA

AF:

0.307

AC:

2643

ExAC

AF:

0.439

AC:

53335

Asia WGS

AF:

0.703

AC:

2441

AN:

3476

EpiCase

AF:

0.312

EpiControl

AF:

0.317

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 15, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Smith-Magenis syndrome

Benign:2

May 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 11, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

0.71

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;D;.

REVEL

Benign

0.079

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.039

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.19

MPC

0.77

ClinPred

0.046

GERP RS

3.6

Varity_R

0.31

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over