Genetic Variant NM_030665.4:c.837G>C (chr17-17793785-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_030665.4(RAI1):c.837G>C(p.Gln279His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAI1
NM_030665.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

Publications

16 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17403415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4 link	c.837G>C	p.Gln279His	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.837G>C	p.Gln279His	missense_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4		Q7Z5J4-1
RAI1	ENST00000395774.1 link	c.837G>C	p.Gln279His	missense_variant	Exon 2 of 2	2		ENSP00000379120.1		A8MXE8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

522202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

254532

African (AFR)

AF:

0.00

AC:

AN:

6352

American (AMR)

AF:

0.00

AC:

AN:

6850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8720

East Asian (EAS)

AF:

0.00

AC:

AN:

848

South Asian (SAS)

AF:

0.00

AC:

AN:

10500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

451470

Other (OTH)

AF:

0.00

AC:

AN:

19228

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

2043

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.6

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.56

T;T;T

M_CAP

Uncertain

0.085

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.1

L;.;.

PhyloP100

2.5

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.97

N;N;.

REVEL

Benign

0.12

Sift

Benign

0.033

D;D;.

Sift4G

Uncertain

0.033

D;D;.

Polyphen

0.99

D;.;.

Vest4

0.27

MutPred

0.15

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;

MVP

0.34

MPC

0.39

ClinPred

0.42

GERP RS

0.17

Varity_R

0.059

gMVP

0.48

Mutation Taster

=89/11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over