rs750872928

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_030665.4(RAI1):c.5264C>A(p.Pro1755His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1755P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0570

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Smith-Magenis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Potocki-Lupski syndrome
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RAI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19619384).

BP6

Variant 17-17798212-C-A is Benign according to our data. Variant chr17-17798212-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 436503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000089 (13/1460056) while in subpopulation SAS AF = 0.000151 (13/86208). AF 95% confidence interval is 0.0000889. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.5264C>A	p.Pro1755His	missense_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.5264C>A	p.Pro1755His	missense_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000583166.1 link	c.-173C>A		upstream_gene_variant		2		ENSP00000463984.1		J3QR08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000206

AC:

AN:

243054

AF XY:

0.0000376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460056

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000151

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111668

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 28, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

T;.

Eigen

Benign

0.045

Eigen_PC

Benign

0.0081

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.64

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.0

L;.

PhyloP100

-0.057

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0080

D;.

Polyphen

0.99

D;.

Vest4

0.29

MutPred

0.16

Loss of catalytic residue at P1754 (P = 0.0116);.;

MVP

0.21

MPC

0.53

ClinPred

0.32

GERP RS

4.6

PromoterAI

0.0096

Neutral

(source)

Varity_R

0.089

gMVP

0.28

Mutation Taster

=93/7

polymorphism

(source)

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

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rs750872928

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over