rs200061071

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_030665.4(RAI1):c.1925C>T(p.Ser642Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S642S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.27

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06749174).

BP6

Variant 17-17794873-C-T is Benign according to our data. Variant chr17-17794873-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000105 (16/152330) while in subpopulation AMR AF= 0.000523 (8/15308). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.1925C>T	p.Ser642Leu	missense_variant	3/6	ENST00000353383.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAI1	ENST00000353383.6 linkuse as main transcript	c.1925C>T	p.Ser642Leu	missense_variant	3/6	1	NM_030665.4	P1	Q7Z5J4-1
RAI1	ENST00000395774.1 linkuse as main transcript	c.1925C>T	p.Ser642Leu	missense_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000918

AC:

AN:

250458

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461022

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	RAI1: BP4 -

RAI1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

The RAI1 c.1925C>T variant is predicted to result in the amino acid substitution p.Ser642Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17698187-C-T), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 27, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.61

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

N;D;.

REVEL

Benign

0.052

Sift

Uncertain

0.0030

D;D;.

Sift4G

Uncertain

0.019

D;T;.

Polyphen

0.99

D;.;.

Vest4

0.33

MVP

0.23

MPC

0.26

ClinPred

0.077

GERP RS

5.4

Varity_R

0.073

gMVP

0.15

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