rs34083643

Variant names:

• chr17-17793787-AG-A
• rs34083643
• NM_030665.4:c.840delG

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.840delG​(p.Gln280HisfsTer84) 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 0.38 (11070 hom., cov: 0)
  • Exomes 𝑓: 0.33 (48739 hom.)
• Consequence: RAI1 NM_030665.4 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.466
• Publications: 13 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-AG-A is Benign according to our data. Variant chr17-17793787-AG-A is described in ClinVar as Benign. ClinVar VariationId is 587783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 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.840delG	p.Gln280HisfsTer84	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.840delG	p.Gln280HisfsTer84	frameshift	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.840delG	p.Gln280HisfsTer84	frameshift	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.840delG	p.Gln280HisfsTer84	frameshift	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 54845 AN: 145638 Hom.: 11075 Cov.: 0

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.237 AC: 42962 AN: 181254 AF XY: 0.241

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.585

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.326 AC: 445687 AN: 1368702 Hom.: 48739 Cov.: 0 AF XY: 0.332 AC XY: 226114 AN XY: 681328

African (AFR) AF: 0.345 AC: 10684 AN: 30970

American (AMR) AF: 0.490 AC: 20902 AN: 42638

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 7680 AN: 23274

East Asian (EAS) AF: 0.645 AC: 24105 AN: 37360

South Asian (SAS) AF: 0.552 AC: 45960 AN: 83242

European-Finnish (FIN) AF: 0.315 AC: 14835 AN: 47092

Middle Eastern (MID) AF: 0.374 AC: 1989 AN: 5322

European-Non Finnish (NFE) AF: 0.288 AC: 299881 AN: 1042738

Other (OTH) AF: 0.350 AC: 19651 AN: 56066

GnomAD4 genome AF: 0.376 AC: 54861 AN: 145752 Hom.: 11070 Cov.: 0 AF XY: 0.389 AC XY: 27738 AN XY: 71326

African (AFR) AF: 0.350 AC: 14232 AN: 40690

American (AMR) AF: 0.478 AC: 7000 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1105 AN: 3104

East Asian (EAS) AF: 0.843 AC: 4257 AN: 5048

South Asian (SAS) AF: 0.701 AC: 3353 AN: 4782

European-Finnish (FIN) AF: 0.352 AC: 3458 AN: 9826

Middle Eastern (MID) AF: 0.326 AC: 90 AN: 276

European-Non Finnish (NFE) AF: 0.314 AC: 20263 AN: 64512

Other (OTH) AF: 0.379 AC: 751 AN: 1984

Alfa AF: 0.000541 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Smith-Magenis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=144/56	disease causing (fs/PTC)

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: rs34083643; hg19: chr17-17697101; COSMIC: COSV55389171; COSMIC: COSV55389171;