rs11649804

Positions:

chr17-17793441-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030665.4(RAI1):c.493C>A(p.Pro165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,504 control chromosomes in the GnomAD database, including 115,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11981 hom., cov: 32)

Exomes 𝑓: 0.35 ( 103887 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.710

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.54322E-7).

BP6

Variant 17-17793441-C-A is Benign according to our data. Variant chr17-17793441-C-A is described in ClinVar as [Benign]. Clinvar id is 96194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17793441-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.493C>A	p.Pro165Thr	missense_variant	3/6	ENST00000353383.6	NP_109590.3	Q7Z5J4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 linkuse as main transcript	c.493C>A	p.Pro165Thr	missense_variant	3/6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 linkuse as main transcript	c.493C>A	p.Pro165Thr	missense_variant	2/2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57083

AN:

151868

Hom.:

11979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.845

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.366

GnomAD3 exomes

AF:

0.443

AC:

111013

AN:

250752

Hom.:

29243

AF XY:

0.447

AC XY:

60621

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.393

Gnomad AMR exome

AF:

0.583

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.852

Gnomad SAS exome

AF:

0.718

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.350

AC:

511481

AN:

1461518

Hom.:

103887

Cov.:

AF XY:

0.360

AC XY:

261888

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.395

Gnomad4 AMR exome

AF:

0.569

Gnomad4 ASJ exome

AF:

0.330

Gnomad4 EAS exome

AF:

0.832

Gnomad4 SAS exome

AF:

0.713

Gnomad4 FIN exome

AF:

0.321

Gnomad4 NFE exome

AF:

0.295

Gnomad4 OTH exome

AF:

0.374

GnomAD4 genome

AF:

0.376

AC:

57111

AN:

151986

Hom.:

11981

Cov.:

AF XY:

0.388

AC XY:

28833

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.381

Gnomad4 AMR

AF:

0.466

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.845

Gnomad4 SAS

AF:

0.724

Gnomad4 FIN

AF:

0.333

Gnomad4 NFE

AF:

0.301

Gnomad4 OTH

AF:

0.364

Alfa

AF:

0.332

Hom.:

22191

Bravo

AF:

0.383

TwinsUK

AF:

0.287

AC:

1064

ALSPAC

AF:

0.297

AC:

1144

ESP6500AA

AF:

0.395

AC:

1742

ESP6500EA

AF:

0.307

AC:

2643

ExAC

AF:

0.439

AC:

53335

Asia WGS

AF:

0.703

AC:

2441

AN:

3476

EpiCase

AF:

0.312

EpiControl

AF:

0.317

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Smith-Magenis syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2017	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;D;.

REVEL

Benign

0.079

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.039

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.19

MPC

0.77

ClinPred

0.046

GERP RS

3.6

Varity_R

0.31

gMVP

0.26

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