rs34083643

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_030665.4(RAI1):c.840delG(p.Gln280HisfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q280Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.38 ( 11070 hom., cov: 0)

Exomes 𝑓: 0.33 ( 48739 hom. )

Consequence

RAI1
NM_030665.4 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.466

Publications

13 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 -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 17-17793787-AG-A is Benign according to our data. Variant chr17-17793787-AG-A is described in ClinVar as [Benign]. Clinvar id is 587783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.840delG	p.Gln280HisfsTer84	frameshift_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.840delG	p.Gln280HisfsTer84	frameshift_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.840delG	p.Gln280HisfsTer84	frameshift_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

54845

AN:

145638

Hom.:

11075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.478

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.843

Gnomad SAS

AF:

0.702

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.381

GnomAD2 exomes

AF:

0.237

AC:

42962

AN:

181254

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.356

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.326

AC:

445687

AN:

1368702

Hom.:

48739

Cov.:

AF XY:

0.332

AC XY:

226114

AN XY:

681328

show subpopulations

African (AFR)

AF:

0.345

AC:

10684

AN:

30970

American (AMR)

AF:

0.490

AC:

20902

AN:

42638

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

7680

AN:

23274

East Asian (EAS)

AF:

0.645

AC:

24105

AN:

37360

South Asian (SAS)

AF:

0.552

AC:

45960

AN:

83242

European-Finnish (FIN)

AF:

0.315

AC:

14835

AN:

47092

Middle Eastern (MID)

AF:

0.374

AC:

1989

AN:

5322

European-Non Finnish (NFE)

AF:

0.288

AC:

299881

AN:

1042738

Other (OTH)

AF:

0.350

AC:

19651

AN:

56066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

15118

30236

45355

60473

75591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.376

AC:

54861

AN:

145752

Hom.:

11070

Cov.:

AF XY:

0.389

AC XY:

27738

AN XY:

71326

show subpopulations

African (AFR)

AF:

0.350

AC:

14232

AN:

40690

American (AMR)

AF:

0.478

AC:

7000

AN:

14646

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1105

AN:

3104

East Asian (EAS)

AF:

0.843

AC:

4257

AN:

5048

South Asian (SAS)

AF:

0.701

AC:

3353

AN:

4782

European-Finnish (FIN)

AF:

0.352

AC:

3458

AN:

9826

Middle Eastern (MID)

AF:

0.326

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.314

AC:

20263

AN:

64512

Other (OTH)

AF:

0.379

AC:

751

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1716

3432

5147

6863

8579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000541

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 29, 2017

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

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

Mutation Taster

=144/56

disease causing (fs/PTC)

(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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rs34083643

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