NM_030665.4:c.870_872dupGCA

Variant names:

• chr17-17793779-C-CCAG
• rs371983878
• NM_030665.4:c.870_872dupGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_030665.4(RAI1):​c.870_872dupGCA​(p.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 0.0212 in 1,356,272 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q291Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (26 hom., cov: 0)
  • Exomes 𝑓: 0.020 (16 hom.)
• Consequence: RAI1 NM_030665.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• 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-CCAG is Benign according to our data. Variant chr17-17793779-C-CCAG is described in ClinVar as Benign. ClinVar VariationId is 130086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 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.870_872dupGCA	p.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.870_872dupGCA	p.Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.870_872dupGCA	p.Gln291dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.870_872dupGCA	p.Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 2599 AN: 78794 Hom.: 27 Cov.: 0

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00533

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.0281

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.0205 AC: 26172 AN: 1277388 Hom.: 16 Cov.: 38 AF XY: 0.0213 AC XY: 13483 AN XY: 631784

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

African (AFR) AF: 0.0140 AC: 399 AN: 28582

American (AMR) AF: 0.0184 AC: 581 AN: 31646

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 386 AN: 23362

East Asian (EAS) AF: 0.00177 AC: 33 AN: 18624

South Asian (SAS) AF: 0.0408 AC: 2271 AN: 55660

European-Finnish (FIN) AF: 0.0188 AC: 866 AN: 46154

Middle Eastern (MID) AF: 0.0292 AC: 142 AN: 4856

European-Non Finnish (NFE) AF: 0.0202 AC: 20540 AN: 1016610

Other (OTH) AF: 0.0184 AC: 954 AN: 51894

⚠️ 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: 0.0329 AC: 2598 AN: 78884 Hom.: 26 Cov.: 0 AF XY: 0.0344 AC XY: 1289 AN XY: 37498

African (AFR) AF: 0.0240 AC: 571 AN: 23824

American (AMR) AF: 0.0351 AC: 206 AN: 5870

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 59 AN: 1966

East Asian (EAS) AF: 0.00535 AC: 4 AN: 748

South Asian (SAS) AF: 0.145 AC: 118 AN: 814

European-Finnish (FIN) AF: 0.0307 AC: 186 AN: 6064

Middle Eastern (MID) AF: 0.0301 AC: 5 AN: 166

European-Non Finnish (NFE) AF: 0.0373 AC: 1418 AN: 37972

Other (OTH) AF: 0.0287 AC: 31 AN: 1080

Alfa AF: 0.0138 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (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; COSMIC: COSV104555111; COSMIC: COSV104555111;