rs113208290

Positions:

chr17-17794090-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.1142C>T(p.Ala381Val) variant causes a missense change. The variant allele was found at a frequency of 0.00445 in 1,614,076 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 28 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.90

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=0.007868499).

BP6

Variant 17-17794090-C-T is Benign according to our data. Variant chr17-17794090-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17794090-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.004 (609/152324) while in subpopulation AMR AF= 0.00811 (124/15296). AF 95% confidence interval is 0.00695. There are 2 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 609 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.1142C>T	p.Ala381Val	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.1142C>T	p.Ala381Val	missense_variant	3/6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 linkuse as main transcript	c.1142C>T	p.Ala381Val	missense_variant	2/2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00382

AC:

959

AN:

251210

Hom.:

AF XY:

0.00378

AC XY:

513

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00449

AC:

6569

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3253

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00512

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.000807

Gnomad4 NFE exome

AF:

0.00493

Gnomad4 OTH exome

AF:

0.00556

GnomAD4 genome

AF:

0.00400

AC:

609

AN:

152324

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00811

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00517

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00362

AC:

440

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RAI1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 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. -

Smith-Magenis syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.094

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0079

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

M;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

N;D;.

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.057

T;T;.

Polyphen

0.98

D;.;.

Vest4

0.51

MVP

0.12

MPC

0.35

ClinPred

0.027

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.39

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