17-17794090-C-T

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.1142C>T(p.Ala381Val) variant causes a missense change. The variant allele was found at a frequency of 0.00445 in 1,614,076 control chromosomes in the GnomAD database, including 30 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. A381G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 28 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.90

Publications

10 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=0.007868499).

BP6

Variant 17-17794090-C-T is Benign according to our data. Variant chr17-17794090-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.004 (609/152324) while in subpopulation AMR AF = 0.00811 (124/15296). AF 95% confidence interval is 0.00695. There are 2 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 609 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.1142C>T	p.Ala381Val	missense_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.1142C>T	p.Ala381Val	missense_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.1142C>T	p.Ala381Val	missense_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00382

AC:

959

AN:

251210

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00449

AC:

6569

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3253

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00512

AC:

229

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

351

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000823

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000807

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00493

AC:

5486

AN:

1112010

Other (OTH)

AF:

0.00556

AC:

336

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

489

979

1468

1958

2447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<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:

0.00400

AC:

609

AN:

152324

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41568

American (AMR)

AF:

0.00811

AC:

124

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00517

AC:

352

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00454

Hom.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00362

AC:

440

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

- -

Dec 22, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Feb 03, 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

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAI1: BP4, BS2 -

Inborn genetic diseases

Benign:1

May 06, 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. -

Smith-Magenis syndrome

Benign:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.094

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0079

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

M;.;.

PhyloP100

3.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

N;D;.

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.057

T;T;.

Polyphen

0.98

D;.;.

Vest4

0.51

MVP

0.12

MPC

0.35

ClinPred

0.027

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.39

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over