rs35068024

Variant names:

• chr17-17793784-AGC-A
• rs35068024
• NM_030665.4:c.837_838delGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_030665.4(RAI1):​c.837_838delGC​(p.Gln280AlafsTer108) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,455,922 control chromosomes in the GnomAD database, including 113,580 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.39 (11743 hom., cov: 0)
  • Exomes 𝑓: 0.39 (101837 hom.)
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.64
• Publications: 15 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 17-17793784-AGC-A is Benign according to our data. Variant chr17-17793784-AGC-A is described in ClinVar as Benign. ClinVar VariationId is 167555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

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.837_838delGC	p.Gln280AlafsTer108	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.837_838delGC	p.Gln280AlafsTer108	frameshift	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.837_838delGC	p.Gln280AlafsTer108	frameshift	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.837_838delGC	p.Gln280AlafsTer108	frameshift	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 56570 AN: 143594 Hom.: 11744 Cov.: 0

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.379 AC: 75378 AN: 198702 AF XY: 0.384

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.741

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.387 AC: 507253 AN: 1312242 Hom.: 101837 AF XY: 0.396 AC XY: 259412 AN XY: 654896

African (AFR) AF: 0.487 AC: 13219 AN: 27158

American (AMR) AF: 0.594 AC: 25378 AN: 42742

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 8616 AN: 22946

East Asian (EAS) AF: 0.844 AC: 32813 AN: 38858

South Asian (SAS) AF: 0.703 AC: 59736 AN: 85004

European-Finnish (FIN) AF: 0.377 AC: 16678 AN: 44272

Middle Eastern (MID) AF: 0.430 AC: 2232 AN: 5190

European-Non Finnish (NFE) AF: 0.329 AC: 326201 AN: 992030

Other (OTH) AF: 0.414 AC: 22380 AN: 54042

GnomAD4 genome AF: 0.394 AC: 56593 AN: 143680 Hom.: 11743 Cov.: 0 AF XY: 0.406 AC XY: 28581 AN XY: 70372

African (AFR) AF: 0.403 AC: 15682 AN: 38920

American (AMR) AF: 0.484 AC: 7073 AN: 14606

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1109 AN: 3088

East Asian (EAS) AF: 0.851 AC: 4291 AN: 5044

South Asian (SAS) AF: 0.707 AC: 3378 AN: 4776

European-Finnish (FIN) AF: 0.361 AC: 3525 AN: 9776

Middle Eastern (MID) AF: 0.336 AC: 92 AN: 274

European-Non Finnish (NFE) AF: 0.316 AC: 20325 AN: 64354

Other (OTH) AF: 0.391 AC: 766 AN: 1958

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=127/73	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: rs35068024; hg19: chr17-17697098; COSMIC: COSV55394436; COSMIC: COSV55394436;