rs150563155

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.61

Publications

17 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=0.004776269).

BP6

Variant 17-17793673-C-T is Benign according to our data. Variant chr17-17793673-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 358 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	NM_030665.4	MANE Select	c.725C>T	p.Pro242Leu	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.725C>T	p.Pro242Leu	missense	Exon 3 of 6	ENSP00000323074.4
RAI1	ENST00000918590.1		c.725C>T	p.Pro242Leu	missense	Exon 2 of 5	ENSP00000588649.1
RAI1	ENST00000955422.1		c.725C>T	p.Pro242Leu	missense	Exon 3 of 6	ENSP00000625481.1

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

GnomAD2 exomes

AF:

0.00298

AC:

738

AN:

247306

AF XY:

0.00347

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 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

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.00237

AC:

106

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00983

AC:

257

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00423

AC:

365

AN:

86258

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

52402

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5768

European-Non Finnish (NFE)

AF:

0.00175

AC:

1946

AN:

1112008

Other (OTH)

AF:

0.00343

AC:

207

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

243

486

730

973

1216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00235

AC:

358

AN:

152274

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41548

American (AMR)

AF:

0.00405

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00273

AC:

186

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00301

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

not specified (2)

Inborn genetic diseases (1)

RAI1-related disorder (1)

Smith-Magenis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Benign

0.038

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.0048

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.2

PhyloP100

1.6

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.22

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

1.0

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

Mutation Taster

=93/7

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over