NM_030665.4:c.840_843delGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.840_843delGCAG(p.Gln280HisfsTer83) 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 0.00096 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00092 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

RAI1
NM_030665.4 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.03

Publications

2 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-AGCAG-A is Benign according to our data. Variant chr17-17793787-AGCAG-A is described in ClinVar as Benign. ClinVar VariationId is 403362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000961 (140/145748) while in subpopulation EAS AF = 0.00337 (17/5048). AF 95% confidence interval is 0.00215. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.840_843delGCAG	p.Gln280HisfsTer83	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.840_843delGCAG	p.Gln280HisfsTer83	frameshift_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.840_843delGCAG	p.Gln280HisfsTer83	frameshift_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

140

AN:

145634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000887

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000547

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00336

Gnomad SAS

AF:

0.00251

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000510

GnomAD2 exomes

AF:

0.0393

AC:

7127

AN:

181254

AF XY:

0.0394

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0561

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0218

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000919

AC:

1176

AN:

1279016

Hom.:

AF XY:

0.00100

AC XY:

633

AN XY:

631838

show subpopulations

African (AFR)

AF:

0.000826

AC:

AN:

29058

American (AMR)

AF:

0.00140

AC:

AN:

35646

Ashkenazi Jewish (ASJ)

AF:

0.0000915

AC:

AN:

21862

East Asian (EAS)

AF:

0.00620

AC:

145

AN:

23404

South Asian (SAS)

AF:

0.00523

AC:

322

AN:

61510

European-Finnish (FIN)

AF:

0.00725

AC:

325

AN:

44834

Middle Eastern (MID)

AF:

0.000398

AC:

AN:

5020

European-Non Finnish (NFE)

AF:

0.000253

AC:

254

AN:

1005490

Other (OTH)

AF:

0.000996

AC:

AN:

52192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000961

AC:

140

AN:

145748

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

71318

show subpopulations

African (AFR)

AF:

0.000884

AC:

AN:

40702

American (AMR)

AF:

0.000546

AC:

AN:

14650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3102

East Asian (EAS)

AF:

0.00337

AC:

AN:

5048

South Asian (SAS)

AF:

0.00251

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00489

AC:

AN:

9814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

64506

Other (OTH)

AF:

0.000504

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: VQSRTrancheINDEL97.00to99.00 (11.52% South Asian) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Aug 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 26, 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 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Mutation Taster

=175/25

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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