rs775735568

Variant names:

• chr17-17793787-AGCAG-A
• rs775735568
• NM_030665.4:c.840_843delGCAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.840_843delGCAG​(p.Gln280HisfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q280Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00092 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.03
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 17-17793787-AGCAG-A is Benign according to our data. Variant chr17-17793787-AGCAG-A is described in ClinVar as Benign. ClinVar VariationId is 403362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000961 (140/145748) while in subpopulation EAS AF = 0.00337 (17/5048). AF 95% confidence interval is 0.00215. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 140 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.840_843delGCAG	p.Gln280HisfsTer83	frameshift	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.840_843delGCAG	p.Gln280HisfsTer83	frameshift	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.840_843delGCAG	p.Gln280HisfsTer83	frameshift	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.840_843delGCAG	p.Gln280HisfsTer83	frameshift	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 140 AN: 145634 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000887

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000547

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00336

Gnomad SAS AF: 0.00251

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000510

GnomAD2 exomes AF: 0.0393 AC: 7127 AN: 181254 AF XY: 0.0394

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0378

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000919 AC: 1176 AN: 1279016 Hom.: 6 AF XY: 0.00100 AC XY: 633 AN XY: 631838

African (AFR) AF: 0.000826 AC: 24 AN: 29058

American (AMR) AF: 0.00140 AC: 50 AN: 35646

Ashkenazi Jewish (ASJ) AF: 0.0000915 AC: 2 AN: 21862

East Asian (EAS) AF: 0.00620 AC: 145 AN: 23404

South Asian (SAS) AF: 0.00523 AC: 322 AN: 61510

European-Finnish (FIN) AF: 0.00725 AC: 325 AN: 44834

Middle Eastern (MID) AF: 0.000398 AC: 2 AN: 5020

European-Non Finnish (NFE) AF: 0.000253 AC: 254 AN: 1005490

Other (OTH) AF: 0.000996 AC: 52 AN: 52192

GnomAD4 genome AF: 0.000961 AC: 140 AN: 145748 Hom.: 1 Cov.: 0 AF XY: 0.00108 AC XY: 77 AN XY: 71318

African (AFR) AF: 0.000884 AC: 36 AN: 40702

American (AMR) AF: 0.000546 AC: 8 AN: 14650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3102

East Asian (EAS) AF: 0.00337 AC: 17 AN: 5048

South Asian (SAS) AF: 0.00251 AC: 12 AN: 4782

European-Finnish (FIN) AF: 0.00489 AC: 48 AN: 9814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000279 AC: 18 AN: 64506

Other (OTH) AF: 0.000504 AC: 1 AN: 1984

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Smith-Magenis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=175/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs775735568; hg19: chr17-17697101;