chr17-17793779-C-CCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.867_872dupGCAGCA(p.Gln290_Gln291dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,357,582 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q291Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00097 ( 0 hom. )

Consequence

RAI1
NM_030665.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.36

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_030665.4

BP6

Variant 17-17793779-C-CCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 589308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00279 (220/78922) while in subpopulation AFR AF = 0.00634 (151/23834). AF 95% confidence interval is 0.00551. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	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.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

219

AN:

78832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00123

Gnomad FIN

AF:

0.000495

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00282

GnomAD4 exome

AF:

0.000968

AC:

1238

AN:

1278660

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

610

AN XY:

632422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00458

AC:

131

AN:

28588

American (AMR)

AF:

0.00114

AC:

AN:

31710

Ashkenazi Jewish (ASJ)

AF:

0.0000428

AC:

AN:

23378

East Asian (EAS)

AF:

0.000268

AC:

AN:

18624

South Asian (SAS)

AF:

0.000932

AC:

AN:

55802

European-Finnish (FIN)

AF:

0.000195

AC:

AN:

46186

Middle Eastern (MID)

AF:

0.00103

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.000935

AC:

951

AN:

1017548

Other (OTH)

AF:

0.000924

AC:

AN:

51958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.00279

AC:

220

AN:

78922

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

AN XY:

37510

show subpopulations

African (AFR)

AF:

0.00634

AC:

151

AN:

23834

American (AMR)

AF:

0.00187

AC:

AN:

5874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1968

East Asian (EAS)

AF:

0.00

AC:

AN:

748

South Asian (SAS)

AF:

0.00122

AC:

AN:

818

European-Finnish (FIN)

AF:

0.000495

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.0181

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

37988

Other (OTH)

AF:

0.00278

AC:

AN:

1080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Bravo

AF:

0.00161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAI1: BS1, BS2 -

Jul 06, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 03, 2021

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

Jul 22, 2019

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

1.4

Mutation Taster

=83/17

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