17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr17-17793779-C-CCAGCAGCAGCAGCAG
• rs371983878
• NM_030665.4:c.858_872dupGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_030665.4(RAI1):​c.858_872dupGCAGCAGCAGCAGCA​(p.Gln287_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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q291Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAI1 NM_030665.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_030665.4
• BP6: Variant 17-17793779-C-CCAGCAGCAGCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAGCAGCAGCAG is described in ClinVar as Likely_benign. ClinVar VariationId is 1480692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000114 (9/78920) while in subpopulation NFE AF = 0.000158 (6/37988). AF 95% confidence interval is 0.0000685. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4	c.858_872dupGCAGCAGCAGCAGCA	p.Gln287_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.858_872dupGCAGCAGCAGCAGCA	p.Gln287_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4
RAI1	ENST00000395774.1	c.858_872dupGCAGCAGCAGCAGCA	p.Gln287_Gln291dup	disruptive_inframe_insertion	Exon 2 of 2	2		ENSP00000379120.1

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 9 AN: 78830 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000158

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000274 AC: 35 AN: 1278792 Hom.: 0 Cov.: 38 AF XY: 0.0000253 AC XY: 16 AN XY: 632478

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

African (AFR) AF: 0.0000350 AC: 1 AN: 28606

American (AMR) AF: 0.00 AC: 0 AN: 31712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23376

East Asian (EAS) AF: 0.00 AC: 0 AN: 18624

South Asian (SAS) AF: 0.0000358 AC: 2 AN: 55804

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 46186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4864

European-Non Finnish (NFE) AF: 0.0000295 AC: 30 AN: 1017658

Other (OTH) AF: 0.0000192 AC: 1 AN: 51962

⚠️ 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.

GnomAD4 genome AF: 0.000114 AC: 9 AN: 78920 Hom.: 0 Cov.: 0 AF XY: 0.0000800 AC XY: 3 AN XY: 37508

African (AFR) AF: 0.000126 AC: 3 AN: 23834

American (AMR) AF: 0.00 AC: 0 AN: 5872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1968

East Asian (EAS) AF: 0.00 AC: 0 AN: 748

South Asian (SAS) AF: 0.00 AC: 0 AN: 818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.000158 AC: 6 AN: 37988

Other (OTH) AF: 0.00 AC: 0 AN: 1080

Alfa AF: 0.00 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=83/17	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371983878; hg19: chr17-17697093;