rs138332224

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.610C>T(p.Pro204Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,912 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 10 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.23

Publications

3 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=0.005404234).

BP6

Variant 17-17793558-C-T is Benign according to our data. Variant chr17-17793558-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152286) while in subpopulation NFE AF = 0.00228 (155/67990). AF 95% confidence interval is 0.00199. There are 2 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 365 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.610C>T	p.Pro204Ser	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.610C>T	p.Pro204Ser	missense	Exon 3 of 6	ENSP00000323074.4
RAI1	ENST00000918590.1		c.610C>T	p.Pro204Ser	missense	Exon 2 of 5	ENSP00000588649.1
RAI1	ENST00000955422.1		c.610C>T	p.Pro204Ser	missense	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00261

AC:

655

AN:

251070

AF XY:

0.00250

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00166

AC:

2429

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1218

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0172

AC:

913

AN:

53170

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00126

AC:

1398

AN:

1111998

Other (OTH)

AF:

0.00127

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

179

358

538

717

896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00240

AC:

365

AN:

152286

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41564

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00228

AC:

155

AN:

67990

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

101

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:

0.00164

Hom.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00222

AC:

269

EpiCase

AF:

0.000981

EpiControl

AF:

0.000830

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 (7)

Inborn genetic diseases (1)

not specified (1)

RAI1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

6.2

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.087

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

PhyloP100

2.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Benign

0.034

Sift

Benign

0.50

Sift4G

Benign

0.87

Polyphen

0.0030

Vest4

0.18

MVP

0.13

MPC

0.27

ClinPred

0.0054

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.045

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over