chr17-17793217-G-C

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.269G>C(p.Gly90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,611,184 control chromosomes in the GnomAD database, including 134,628 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G90V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.45 ( 17645 hom., cov: 32)

Exomes 𝑓: 0.37 ( 116983 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.227

Publications

43 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=5.835128E-7).

BP6

Variant 17-17793217-G-C is Benign according to our data. Variant chr17-17793217-G-C is described in ClinVar as Benign. ClinVar VariationId is 96183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	NM_030665.4	MANE Select	c.269G>C	p.Gly90Ala	missense	Exon 3 of 6	NP_109590.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAI1	ENST00000353383.6	TSL:1 MANE Select	c.269G>C	p.Gly90Ala	missense	Exon 3 of 6	ENSP00000323074.4
RAI1	ENST00000395774.1	TSL:2	c.269G>C	p.Gly90Ala	missense	Exon 2 of 2	ENSP00000379120.1
RAI1	ENST00000471135.2	TSL:3	c.*74G>C		downstream_gene	N/A	ENSP00000463607.1

Frequencies

GnomAD3 genomes

AF:

0.452

AC:

68553

AN:

151762

Hom.:

17624

Cov.:

show subpopulations

Gnomad AFR

AF:

0.608

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.357

Gnomad EAS

AF:

0.917

Gnomad SAS

AF:

0.757

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.438

GnomAD2 exomes

AF:

0.480

AC:

116099

AN:

242094

AF XY:

0.479

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.603

Gnomad ASJ exome

AF:

0.369

Gnomad EAS exome

AF:

0.923

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.368

AC:

536943

AN:

1459304

Hom.:

116983

Cov.:

AF XY:

0.378

AC XY:

274420

AN XY:

725830

show subpopulations

African (AFR)

AF:

0.626

AC:

20926

AN:

33452

American (AMR)

AF:

0.592

AC:

26339

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

9459

AN:

26070

East Asian (EAS)

AF:

0.920

AC:

36491

AN:

39666

South Asian (SAS)

AF:

0.745

AC:

64157

AN:

86120

European-Finnish (FIN)

AF:

0.337

AC:

17636

AN:

52374

Middle Eastern (MID)

AF:

0.440

AC:

2527

AN:

5740

European-Non Finnish (NFE)

AF:

0.301

AC:

334822

AN:

1111092

Other (OTH)

AF:

0.408

AC:

24586

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

21818

43636

65455

87273

109091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11476

22952

34428

45904

57380

<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:

0.452

AC:

68612

AN:

151880

Hom.:

17645

Cov.:

AF XY:

0.463

AC XY:

34388

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.608

AC:

25184

AN:

41420

American (AMR)

AF:

0.510

AC:

7784

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1241

AN:

3472

East Asian (EAS)

AF:

0.917

AC:

4690

AN:

5116

South Asian (SAS)

AF:

0.756

AC:

3632

AN:

4806

European-Finnish (FIN)

AF:

0.349

AC:

3693

AN:

10568

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.309

AC:

20998

AN:

67906

Other (OTH)

AF:

0.436

AC:

920

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1751

3502

5253

7004

8755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.347

Hom.:

3233

Bravo

AF:

0.469

TwinsUK

AF:

0.290

AC:

1077

ALSPAC

AF:

0.302

AC:

1165

ESP6500AA

AF:

0.608

AC:

2664

ESP6500EA

AF:

0.312

AC:

2677

ExAC

AF:

0.474

AC:

57345

Asia WGS

AF:

0.760

AC:

2640

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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.

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 15, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.2

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.044

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.16

MetaRNN

Benign

5.8e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.6

PhyloP100

-0.23

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.38

REVEL

Benign

0.071

Sift

Benign

1.0

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.011

MPC

0.29

ClinPred

0.0031

GERP RS

1.1

Varity_R

0.036

gMVP

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over