rs775735568

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.840_843delGCAG(p.Gln280HisfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q280Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00092 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

RAI1
NM_030665.4 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 17-17793787-AGCAG-A is Benign according to our data. Variant chr17-17793787-AGCAG-A is described in ClinVar as [Benign]. Clinvar id is 403362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793787-AGCAG-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000961 (140/145748) while in subpopulation EAS AF= 0.00337 (17/5048). AF 95% confidence interval is 0.00215. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.840_843delGCAG	p.Gln280HisfsTer83	frameshift_variant	Exon 3 of 6	ENST00000353383.6	NP_109590.3	Q7Z5J4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 link	c.840_843delGCAG	p.Gln280HisfsTer83	frameshift_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.840_843delGCAG	p.Gln280HisfsTer83	frameshift_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

140

AN:

145634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000887

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000547

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00336

Gnomad SAS

AF:

0.00251

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000510

GnomAD3 exomes

AF:

0.0393

AC:

7127

AN:

181254

Hom.:

653

AF XY:

0.0394

AC XY:

3925

AN XY:

99682

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0561

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.102

Gnomad SAS exome

AF:

0.0816

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0218

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000919

AC:

1176

AN:

1279016

Hom.:

AF XY:

0.00100

AC XY:

633

AN XY:

631838

show subpopulations

Gnomad4 AFR exome

AF:

0.000826

Gnomad4 AMR exome

AF:

0.00140

Gnomad4 ASJ exome

AF:

0.0000915

Gnomad4 EAS exome

AF:

0.00620

Gnomad4 SAS exome

AF:

0.00523

Gnomad4 FIN exome

AF:

0.00725

Gnomad4 NFE exome

AF:

0.000253

Gnomad4 OTH exome

AF:

0.000996

GnomAD4 genome

AF:

0.000961

AC:

140

AN:

145748

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

71318

show subpopulations

Gnomad4 AFR

AF:

0.000884

Gnomad4 AMR

AF:

0.000546

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00337

Gnomad4 SAS

AF:

0.00251

Gnomad4 FIN

AF:

0.00489

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000504

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: VQSRTrancheINDEL97.00to99.00 (11.52% South Asian) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 26, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Smith-Magenis syndrome

Benign:1

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over