rs3818717

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_030665.4(RAI1):​c.5601T>C​(p.Ile1867Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,612,858 control chromosomes in the GnomAD database, including 229,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 15623 hom., cov: 33)
Exomes 𝑓: 0.52 ( 214154 hom. )

Consequence

RAI1
NM_030665.4 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -1.76

Publications

42 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (REVEL=0.031).
BP6
Variant 17-17803791-T-C is Benign according to our data. Variant chr17-17803791-T-C is described in ClinVar as [Benign]. Clinvar id is 96195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.76 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAI1NM_030665.4 linkc.5601T>C p.Ile1867Ile synonymous_variant Exon 4 of 6 ENST00000353383.6 NP_109590.3 Q7Z5J4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAI1ENST00000353383.6 linkc.5601T>C p.Ile1867Ile synonymous_variant Exon 4 of 6 1 NM_030665.4 ENSP00000323074.4 Q7Z5J4-1
RAI1ENST00000583166.1 linkc.165T>C p.Ile55Ile synonymous_variant Exon 2 of 2 2 ENSP00000463984.1 J3QR08

Frequencies

GnomAD3 genomes
AF:
0.417
AC:
63339
AN:
152034
Hom.:
15622
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.196
Gnomad AMI
AF:
0.524
Gnomad AMR
AF:
0.391
Gnomad ASJ
AF:
0.530
Gnomad EAS
AF:
0.0774
Gnomad SAS
AF:
0.207
Gnomad FIN
AF:
0.513
Gnomad MID
AF:
0.519
Gnomad NFE
AF:
0.574
Gnomad OTH
AF:
0.433
GnomAD2 exomes
AF:
0.423
AC:
106132
AN:
250822
AF XY:
0.425
show subpopulations
Gnomad AFR exome
AF:
0.179
Gnomad AMR exome
AF:
0.329
Gnomad ASJ exome
AF:
0.529
Gnomad EAS exome
AF:
0.0747
Gnomad FIN exome
AF:
0.525
Gnomad NFE exome
AF:
0.570
Gnomad OTH exome
AF:
0.466
GnomAD4 exome
AF:
0.523
AC:
764604
AN:
1460706
Hom.:
214154
Cov.:
51
AF XY:
0.516
AC XY:
374683
AN XY:
726666
show subpopulations
African (AFR)
AF:
0.178
AC:
5951
AN:
33470
American (AMR)
AF:
0.336
AC:
15026
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.532
AC:
13891
AN:
26132
East Asian (EAS)
AF:
0.0778
AC:
3088
AN:
39698
South Asian (SAS)
AF:
0.215
AC:
18549
AN:
86252
European-Finnish (FIN)
AF:
0.528
AC:
27780
AN:
52652
Middle Eastern (MID)
AF:
0.460
AC:
2655
AN:
5766
European-Non Finnish (NFE)
AF:
0.583
AC:
648365
AN:
1111650
Other (OTH)
AF:
0.485
AC:
29299
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
19313
38626
57940
77253
96566
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
17404
34808
52212
69616
87020
<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:
0.416
AC:
63350
AN:
152152
Hom.:
15623
Cov.:
33
AF XY:
0.407
AC XY:
30254
AN XY:
74398
show subpopulations
African (AFR)
AF:
0.196
AC:
8121
AN:
41518
American (AMR)
AF:
0.391
AC:
5973
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.530
AC:
1838
AN:
3470
East Asian (EAS)
AF:
0.0772
AC:
400
AN:
5180
South Asian (SAS)
AF:
0.208
AC:
1003
AN:
4828
European-Finnish (FIN)
AF:
0.513
AC:
5431
AN:
10584
Middle Eastern (MID)
AF:
0.531
AC:
156
AN:
294
European-Non Finnish (NFE)
AF:
0.574
AC:
39042
AN:
67974
Other (OTH)
AF:
0.431
AC:
910
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1685
3369
5054
6738
8423
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
570
1140
1710
2280
2850
<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:
0.516
Hom.:
33053
Bravo
AF:
0.399
Asia WGS
AF:
0.176
AC:
613
AN:
3478
EpiCase
AF:
0.557
EpiControl
AF:
0.556

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

- -

Dec 22, 2014
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
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

- -

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jul 31, 2018
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

- -

Smith-Magenis syndrome Benign:2
Nov 07, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 03, 2017
Athena Diagnostics
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
-0.77
CADD
Benign
4.9
DANN
Benign
0.71
PhyloP100
-1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs3818717; hg19: chr17-17707105; COSMIC: COSV55393781; API