chr17-17793779-C-CCAGCAG

Variant names:

• chr17-17793779-C-CCAGCAG
• rs371983878
• NM_030665.4:c.867_872dupGCAGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_030665.4(RAI1):​c.867_872dupGCAGCA​(p.Gln290_Gln291dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,357,582 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q291Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: RAI1 NM_030665.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.36
• Publications: 8 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_030665.4
• BP6: Variant 17-17793779-C-CCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 589308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00279 (220/78922) while in subpopulation AFR AF = 0.00634 (151/23834). AF 95% confidence interval is 0.00551. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 220 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.867_872dupGCAGCA	p.Gln290_Gln291dup	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.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 219 AN: 78832 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00123

Gnomad FIN AF: 0.000495

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00282

GnomAD4 exome AF: 0.000968 AC: 1238 AN: 1278660 Hom.: 0 Cov.: 38 AF XY: 0.000965 AC XY: 610 AN XY: 632422

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00458 AC: 131 AN: 28588

American (AMR) AF: 0.00114 AC: 36 AN: 31710

Ashkenazi Jewish (ASJ) AF: 0.0000428 AC: 1 AN: 23378

East Asian (EAS) AF: 0.000268 AC: 5 AN: 18624

South Asian (SAS) AF: 0.000932 AC: 52 AN: 55802

European-Finnish (FIN) AF: 0.000195 AC: 9 AN: 46186

Middle Eastern (MID) AF: 0.00103 AC: 5 AN: 4866

European-Non Finnish (NFE) AF: 0.000935 AC: 951 AN: 1017548

Other (OTH) AF: 0.000924 AC: 48 AN: 51958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00279 AC: 220 AN: 78922 Hom.: 1 Cov.: 0 AF XY: 0.00235 AC XY: 88 AN XY: 37510

African (AFR) AF: 0.00634 AC: 151 AN: 23834

American (AMR) AF: 0.00187 AC: 11 AN: 5874

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 748

South Asian (SAS) AF: 0.00122 AC: 1 AN: 818

European-Finnish (FIN) AF: 0.000495 AC: 3 AN: 6066

Middle Eastern (MID) AF: 0.0181 AC: 3 AN: 166

European-Non Finnish (NFE) AF: 0.00126 AC: 48 AN: 37988

Other (OTH) AF: 0.00278 AC: 3 AN: 1080

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00161

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (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: rs371983878; hg19: chr17-17697093;