rs398124417

Variant names:

• chr17-17796723-AAGG-A
• rs149716029
• NM_030665.4:c.3781_3783delGAG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.3781_3783delGAG​(p.Glu1261del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,613,430 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1261E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (32 hom.)
• Consequence: RAI1 NM_030665.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.59
• Publications: 4 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_030665.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-17796723-AAGG-A is Benign according to our data. Variant chr17-17796723-AAGG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00371 (564/152224) while in subpopulation NFE AF = 0.00542 (369/68024). AF 95% confidence interval is 0.00497. There are 7 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 564 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.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	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.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.3781_3783delGAG	p.Glu1261del	conservative_inframe_deletion	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152106 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00278 AC: 696 AN: 250626 AF XY: 0.00279

Gnomad AFR exome AF: 0.000990

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00499 AC: 7288 AN: 1461206 Hom.: 32 AF XY: 0.00490 AC XY: 3559 AN XY: 726860

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.00121 AC: 54 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00351 AC: 186 AN: 52926

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00612 AC: 6801 AN: 1111858

Other (OTH) AF: 0.00359 AC: 217 AN: 60372

GnomAD4 genome AF: 0.00371 AC: 564 AN: 152224 Hom.: 7 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74422

African (AFR) AF: 0.00123 AC: 51 AN: 41518

American (AMR) AF: 0.00150 AC: 23 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00542 AC: 369 AN: 68024

Other (OTH) AF: 0.00285 AC: 6 AN: 2104

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00363

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	not specified (3)
-	-	3	Smith-Magenis syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	RAI1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=81/19	polymorphism

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: rs149716029; hg19: chr17-17700037;