17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

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

The NM_030665.4(RAI1):c.861_872dupGCAGCAGCAGCA(p.Gln288_Gln291dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. Q291Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAI1
NM_030665.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_030665.4

BP6

Variant 17-17793779-C-CCAGCAGCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAGCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212014.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00276 (218/78920) while in subpopulation NFE AF = 0.00398 (151/37986). AF 95% confidence interval is 0.00346. There are 1 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.861_872dupGCAGCAGCAGCA	p.Gln288_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.861_872dupGCAGCAGCAGCA	p.Gln288_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.861_872dupGCAGCAGCAGCA	p.Gln288_Gln291dup	disruptive_inframe_insertion	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

218

AN:

78830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000505

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00965

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00123

Gnomad FIN

AF:

0.00429

Gnomad MID

AF:

0.0112

Gnomad NFE

AF:

0.00398

Gnomad OTH

AF:

0.00188

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00148

AC:

1896

AN:

1277840

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

976

AN XY:

632026

show subpopulations

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

African (AFR)

AF:

0.000350

AC:

AN:

28606

American (AMR)

AF:

0.000631

AC:

AN:

31710

Ashkenazi Jewish (ASJ)

AF:

0.00557

AC:

130

AN:

23338

East Asian (EAS)

AF:

0.00

AC:

AN:

18624

South Asian (SAS)

AF:

0.0000717

AC:

AN:

55804

European-Finnish (FIN)

AF:

0.00234

AC:

108

AN:

46180

Middle Eastern (MID)

AF:

0.000823

AC:

AN:

4862

European-Non Finnish (NFE)

AF:

0.00153

AC:

1552

AN:

1016784

Other (OTH)

AF:

0.00131

AC:

AN:

51932

⚠️ 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: 0.349

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.00276

AC:

218

AN:

78920

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

AN XY:

37510

show subpopulations

African (AFR)

AF:

0.000503

AC:

AN:

23834

American (AMR)

AF:

0.000851

AC:

AN:

5874

Ashkenazi Jewish (ASJ)

AF:

0.00965

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:

0.00429

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00398

AC:

151

AN:

37986

Other (OTH)

AF:

0.00185

AC:

AN:

1080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00252

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Feb 17, 2014

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAI1: BS1, BS2 -

Feb 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

- -

May 12, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 10, 2018

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

Sep 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Intellectual disability

Benign:1

Jul 27, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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