rs200719553

Positions:

• chr17-17796537-G-A
• chr17-17796537-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030665.4(RAI1):​c.3589G>A​(p.Gly1197Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,786 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17780125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI1	NM_030665.4	c.3589G>A	p.Gly1197Ser	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	c.3589G>A	p.Gly1197Ser	missense_variant	3/6	1	NM_030665.4	ENSP00000323074	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458786 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 725730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2021

This variant has not been reported in the literature in individuals with RAI1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1197 of the RAI1 protein (p.Gly1197Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.83	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.46	N;.
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.98	T;.
Polyphen		1.0	D;.
Vest4		0.35
MutPred		0.22		Gain of phosphorylation at G1197 (P = 0.0132);.;
MVP		0.44
MPC		0.54
ClinPred		0.69	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17699851; COSMIC: COSV104555148; COSMIC: COSV104555148;