rs104894634

Variant names:

• chr17-17797633-A-C
• rs104894634
• NM_030665.4:c.4685A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-17797633-A-C
• chr17-17797633-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_030665.4(RAI1):​c.4685A>C​(p.Gln1562Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1562R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 10 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-17797633-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2950.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12256849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAI1	NM_030665.4	c.4685A>C	p.Gln1562Pro	missense_variant	Exon 3 of 6	ENST00000353383.6	NP_109590.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI1	ENST00000353383.6	c.4685A>C	p.Gln1562Pro	missense_variant	Exon 3 of 6	1	NM_030665.4	ENSP00000323074.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		0.24
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.60	N;.
REVEL	Benign	0.13
Sift	Benign	0.17	T;.
Sift4G	Benign	0.34	T;.
Polyphen		0.97	D;.
Vest4		0.46
MutPred		0.23		Loss of MoRF binding (P = 0.0734);.;
MVP		0.50
MPC		0.47
ClinPred		0.29	T
GERP RS		3.6
Varity_R		0.061
gMVP		0.36
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs104894634; hg19: chr17-17700947;