NM_030665.4:c.980C>G

Variant names:

• chr17-17793928-C-G
• rs1555565043
• NM_030665.4:c.980C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_030665.4(RAI1):​c.980C>G​(p.Ala327Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A327A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAI1 NM_030665.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.54
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Potocki-Lupski syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18094212).
• BP6: Variant 17-17793928-C-G is Benign according to our data. Variant chr17-17793928-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436494.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	NM_030665.4	MANE Select	c.980C>G	p.Ala327Gly	missense	Exon 3 of 6	NP_109590.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI1	ENST00000353383.6	TSL:1 MANE Select	c.980C>G	p.Ala327Gly	missense	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.980C>G	p.Ala327Gly	missense	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.980C>G	p.Ala327Gly	missense	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 94

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.059
Sift	Benign	0.064	T
Sift4G	Benign	0.33	T
Polyphen		0.19	B
Vest4		0.27
MutPred		0.34		Loss of stability (P = 0.0053)
MVP		0.082
MPC		0.30
ClinPred		0.29	T
GERP RS		4.6
Varity_R		0.065
gMVP		0.15
Mutation Taster		=91/9	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: rs1555565043; hg19: chr17-17697242;