17-17793057-G-A

Position:

chr17-17793057-G-A

Variant summary

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

The NM_030665.4(RAI1):c.109G>A(p.Gly37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,158 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).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.92

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=0.065570295).

BP6

Variant 17-17793057-G-A is Benign according to our data. Variant chr17-17793057-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436491.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00021 (32/152326) while in subpopulation AFR AF= 0.000698 (29/41566). AF 95% confidence interval is 0.000498. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	3/6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	3/6	1	NM_030665.4	ENSP00000323074	P1	Q7Z5J4-1
RAI1	ENST00000395774.1 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	2/2	2		ENSP00000379120
RAI1	ENST00000471135.2 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	4/4	3		ENSP00000463607

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000998

AC:

AN:

250610

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.000873

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000210

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 13, 2016

- -

Smith-Magenis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 18, 2019

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2019

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

RAI1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.86

D;T;D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.066

T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

N;.;D;.

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0070

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.65

MutPred

0.23

Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);

MVP

0.15

MPC

0.47

ClinPred

0.081

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.29

gMVP

0.20

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