NM_030665.4:c.867_872dupGCAGCA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. 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 (★★).

• 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:5
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 17-17793779-C-CCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4	c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4
RAI1	ENST00000395774.1	c.867_872dupGCAGCA	p.Gln290_Gln291dup	disruptive_inframe_insertion	Exon 2 of 2	2		ENSP00000379120.1

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

Gnomad4 AFR exome AF: 0.00458

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0000428

Gnomad4 EAS exome AF: 0.000268

Gnomad4 SAS exome AF: 0.000932

Gnomad4 FIN exome AF: 0.000195

Gnomad4 NFE exome AF: 0.000935

Gnomad4 OTH exome AF: 0.000924

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

Gnomad4 AFR AF: 0.00634

Gnomad4 AMR AF: 0.00187

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00122

Gnomad4 FIN AF: 0.000495

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.00278

Bravo AF: 0.00161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAI1: BS1, BS2 -

Jul 06, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 03, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RAI1-related disorder Benign:1

Jul 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371983878; hg19: chr17-17697093;