17-17793779-CCAG-C

Position:

• chr17-17793779-CCAG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_030665.4(RAI1):​c.870_872del​(p.Gln291del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 1,213,010 control chromosomes in the GnomAD database, including 1,268 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (912 hom., cov: 0)
  • Exomes 𝑓: 0.077 (356 hom.)
• Consequence: RAI1 NM_030665.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.55

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-CCAG-C is Benign according to our data. Variant chr17-17793779-CCAG-C is described in ClinVar as [Benign]. Clinvar id is 196559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793779-CCAG-C is described in Lovd as [Likely_benign]. Variant chr17-17793779-CCAG-C is described in Lovd as [Benign]. Variant chr17-17793779-CCAG-C is described in Lovd as [Likely_benign]. Variant chr17-17793779-CCAG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.870_872del	p.Gln291del	inframe_deletion	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.870_872del	p.Gln291del	inframe_deletion	3/6	1	NM_030665.4	ENSP00000323074	P1
RAI1	ENST00000395774.1	c.870_872del	p.Gln291del	inframe_deletion	2/2	2		ENSP00000379120

Frequencies

GnomAD3 genomes AF: 0.171 AC: 13457 AN: 78480 Hom.: 900 Cov.: 0

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.0476

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.0768 AC: 87122 AN: 1134446 Hom.: 356 AF XY: 0.0759 AC XY: 42355 AN XY: 558228

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0647

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.00524

Gnomad4 SAS exome AF: 0.0364

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.0741

Gnomad4 OTH exome AF: 0.0839

GnomAD4 genome AF: 0.172 AC: 13499 AN: 78564 Hom.: 912 Cov.: 0 AF XY: 0.174 AC XY: 6512 AN XY: 37326

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2016

This alteration is classified as 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

Jul 19, 2022

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). -

Smith-Magenis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

African/African American population allele frequency is 30.36% (rs74986416, 1586/5010 alleles, 148 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs371983878; hg19: chr17-17697093;