17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr17-17793779-CCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_030665.4(RAI1):​c.861_872dup​(p.Gln288_Gln291dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAI1 NM_030665.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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 -9 ACMG points.

• BP6: Variant 17-17793779-C-CCAGCAGCAGCAG is Benign according to our data. Variant chr17-17793779-C-CCAGCAGCAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (218/78920) while in subpopulation NFE AF= 0.00398 (151/37986). AF 95% confidence interval is 0.00346. There are 1 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.861_872dup	p.Gln288_Gln291dup	inframe_insertion	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.861_872dup	p.Gln288_Gln291dup	inframe_insertion	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.861_872dup	p.Gln288_Gln291dup	inframe_insertion	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 218 AN: 78830 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00965

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00123

Gnomad FIN AF: 0.00429

Gnomad MID AF: 0.0112

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00188

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00148 AC: 1896 AN: 1277840 Hom.: 0 Cov.: 38 AF XY: 0.00154 AC XY: 976 AN XY: 632026

Gnomad4 AFR exome AF: 0.000350

Gnomad4 AMR exome AF: 0.000631

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000717

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00276 AC: 218 AN: 78920 Hom.: 1 Cov.: 0 AF XY: 0.00232 AC XY: 87 AN XY: 37510

Gnomad4 AFR AF: 0.000503

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00965

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00122

Gnomad4 FIN AF: 0.00429

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00185

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RAI1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 12, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2018

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as 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;