rs587780428

Variant names:

• chr17-17793779-C-CCAGCAA
• rs587780428
• NM_030665.4:c.836_837insACAGCA

Your query was ambiguous. Multiple possible variants found:

• chr17-17793779-C-CCAGCAA
• chr17-17793779-C-CCAGCAACAGCAG
• chr17-17793779-C-CCAGCAACAGCAGCAG
• chr17-17793779-C-CCAGCAACAG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_030665.4(RAI1):​c.836_837insACAGCA​(p.Gln279_Gln280insGlnGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,357,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000038 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAI1 NM_030665.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.36
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Potocki-Lupski syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_030665.4
• BP6: Variant 17-17793779-C-CCAGCAA is Benign according to our data. Variant chr17-17793779-C-CCAGCAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1399005.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	NM_030665.4	MANE Select	c.836_837insACAGCA	p.Gln279_Gln280insGlnGln	disruptive_inframe_insertion	Exon 3 of 6	NP_109590.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	ENST00000353383.6	TSL:1 MANE Select	c.836_837insACAGCA	p.Gln279_Gln280insGlnGln	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.836_837insACAGCA	p.Gln279_Gln280insGlnGln	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.836_837insACAGCA	p.Gln279_Gln280insGlnGln	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.0000381 AC: 3 AN: 78832 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000170

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: 0.0000263

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 15 AN: 1278812 Hom.: 0 Cov.: 38 AF XY: 0.0000158 AC XY: 10 AN XY: 632490

African (AFR) AF: 0.00 AC: 0 AN: 28608

American (AMR) AF: 0.0000631 AC: 2 AN: 31712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23378

East Asian (EAS) AF: 0.000107 AC: 2 AN: 18624

South Asian (SAS) AF: 0.0000896 AC: 5 AN: 55806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46186

Middle Eastern (MID) AF: 0.000206 AC: 1 AN: 4866

European-Non Finnish (NFE) AF: 0.00000295 AC: 3 AN: 1017670

Other (OTH) AF: 0.0000385 AC: 2 AN: 51962

GnomAD4 genome AF: 0.0000381 AC: 3 AN: 78832 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 37424

African (AFR) AF: 0.0000421 AC: 1 AN: 23752

American (AMR) AF: 0.000170 AC: 1 AN: 5872

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 750

South Asian (SAS) AF: 0.00 AC: 0 AN: 816

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.0000263 AC: 1 AN: 37988

Other (OTH) AF: 0.00 AC: 0 AN: 1062

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	RAI1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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: rs587780428; hg19: chr17-17697093;