rs8067439

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_030665.4(RAI1):c.1992G>A(p.Pro664Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,613,474 control chromosomes in the GnomAD database, including 291,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25281 hom., cov: 34)

Exomes 𝑓: 0.59 ( 265761 hom. )

Consequence

RAI1
NM_030665.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.42

Publications

34 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-17794940-G-A is Benign according to our data. Variant chr17-17794940-G-A is described in ClinVar as Benign. ClinVar VariationId is 96179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.1992G>A	p.Pro664Pro	synonymous_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.1992G>A	p.Pro664Pro	synonymous_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.1992G>A	p.Pro664Pro	synonymous_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85946

AN:

152060

Hom.:

25254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.577

Gnomad AMI

AF:

0.548

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.562

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.581

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.630

Gnomad OTH

AF:

0.564

GnomAD2 exomes

AF:

0.502

AC:

125894

AN:

250822

AF XY:

0.498

show subpopulations

Gnomad AFR exome

AF:

0.569

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.628

Gnomad OTH exome

AF:

0.537

GnomAD4 exome

AF:

0.590

AC:

861867

AN:

1461296

Hom.:

265761

Cov.:

108

AF XY:

0.580

AC XY:

421992

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.561

AC:

18782

AN:

33480

American (AMR)

AF:

0.387

AC:

17315

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

14540

AN:

26134

East Asian (EAS)

AF:

0.167

AC:

6649

AN:

39700

South Asian (SAS)

AF:

0.267

AC:

22997

AN:

86256

European-Finnish (FIN)

AF:

0.598

AC:

31596

AN:

52872

Middle Eastern (MID)

AF:

0.542

AC:

3125

AN:

5768

European-Non Finnish (NFE)

AF:

0.641

AC:

712654

AN:

1111982

Other (OTH)

AF:

0.566

AC:

34209

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

24960

49921

74881

99842

124802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18526

37052

55578

74104

92630

<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:

0.565

AC:

86029

AN:

152178

Hom.:

25281

Cov.:

AF XY:

0.554

AC XY:

41192

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.577

AC:

23956

AN:

41536

American (AMR)

AF:

0.471

AC:

7204

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.562

AC:

1950

AN:

3470

East Asian (EAS)

AF:

0.153

AC:

789

AN:

5162

South Asian (SAS)

AF:

0.256

AC:

1238

AN:

4828

European-Finnish (FIN)

AF:

0.581

AC:

6146

AN:

10584

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.631

AC:

42862

AN:

67980

Other (OTH)

AF:

0.566

AC:

1198

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1901

3802

5702

7603

9504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.607

Hom.:

52692

Bravo

AF:

0.559

Asia WGS

AF:

0.282

AC:

984

AN:

3478

EpiCase

AF:

0.618

EpiControl

AF:

0.611

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 22, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Smith-Magenis syndrome

Benign:2

May 05, 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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0050

(source)

DANN

Benign

0.52

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

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