17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_030665.4(RAI1):c.852_872delGCAGCAGCAGCAGCAGCAGCA(p.Gln285_Gln291del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000419 in 1,357,644 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q284Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00041 ( 3 hom. )

Consequence

RAI1
NM_030665.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.86

Publications

8 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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_030665.4

BP6

Variant 17-17793779-CCAGCAGCAGCAGCAGCAGCAG-C is Benign according to our data. Variant chr17-17793779-CCAGCAGCAGCAGCAGCAGCAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96200.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000622 (49/78832) while in subpopulation SAS AF = 0.00245 (2/816). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.852_872delGCAGCAGCAGCAGCAGCAGCA	p.Gln285_Gln291del	disruptive_inframe_deletion	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.852_872delGCAGCAGCAGCAGCAGCAGCA	p.Gln285_Gln291del	disruptive_inframe_deletion	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.852_872delGCAGCAGCAGCAGCAGCAGCA	p.Gln285_Gln291del	disruptive_inframe_deletion	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.000622

AC:

AN:

78832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000463

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00102

Gnomad ASJ

AF:

0.00102

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00245

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00562

Gnomad NFE

AF:

0.000658

Gnomad OTH

AF:

0.00188

GnomAD4 exome

AF:

0.000407

AC:

520

AN:

1278812

Hom.:

AF XY:

0.000392

AC XY:

248

AN XY:

632490

show subpopulations

African (AFR)

AF:

0.000350

AC:

AN:

28608

American (AMR)

AF:

0.000662

AC:

AN:

31712

Ashkenazi Jewish (ASJ)

AF:

0.000257

AC:

AN:

23378

East Asian (EAS)

AF:

0.0000537

AC:

AN:

18624

South Asian (SAS)

AF:

0.000484

AC:

AN:

55806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46186

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.000349

AC:

355

AN:

1017670

Other (OTH)

AF:

0.000905

AC:

AN:

51962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

113

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:

0.000622

AC:

AN:

78832

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

AN XY:

37424

show subpopulations

African (AFR)

AF:

0.000463

AC:

AN:

23752

American (AMR)

AF:

0.00102

AC:

AN:

5872

Ashkenazi Jewish (ASJ)

AF:

0.00102

AC:

AN:

1968

East Asian (EAS)

AF:

0.00

AC:

AN:

750

South Asian (SAS)

AF:

0.00245

AC:

AN:

816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.00562

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.000658

AC:

AN:

37988

Other (OTH)

AF:

0.00188

AC:

AN:

1062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAI1: BS1 -

Apr 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 14, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

RAI1-related disorder

Benign:1

Apr 06, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.9

Mutation Taster

=163/37

polymorphism

(source)

Splicing

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