NM_030665.4:c.4311T>C

Variant names:

• chr17-17797259-T-C
• rs4925112
• NM_030665.4:c.4311T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030665.4(RAI1):​c.4311T>C​(p.Pro1437Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,612,960 control chromosomes in the GnomAD database, including 5,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1534 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3553 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.11
• Publications: 14 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 17-17797259-T-C is Benign according to our data. Variant chr17-17797259-T-C is described in ClinVar as Benign. ClinVar VariationId is 96190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

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.4311T>C	p.Pro1437Pro	synonymous	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.4311T>C	p.Pro1437Pro	synonymous	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.4311T>C	p.Pro1437Pro	synonymous	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.4311T>C	p.Pro1437Pro	synonymous	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16435 AN: 151972 Hom.: 1522 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0943

GnomAD2 exomes AF: 0.0605 AC: 15096 AN: 249448 AF XY: 0.0568

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00285

Gnomad FIN exome AF: 0.0783

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0606 AC: 88581 AN: 1460870 Hom.: 3553 Cov.: 37 AF XY: 0.0587 AC XY: 42660 AN XY: 726728

African (AFR) AF: 0.248 AC: 8298 AN: 33480

American (AMR) AF: 0.0386 AC: 1727 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 674 AN: 26136

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39700

South Asian (SAS) AF: 0.0270 AC: 2329 AN: 86256

European-Finnish (FIN) AF: 0.0763 AC: 4003 AN: 52442

Middle Eastern (MID) AF: 0.0519 AC: 299 AN: 5756

European-Non Finnish (NFE) AF: 0.0605 AC: 67281 AN: 1112002

Other (OTH) AF: 0.0645 AC: 3893 AN: 60376

GnomAD4 genome AF: 0.108 AC: 16486 AN: 152090 Hom.: 1534 Cov.: 33 AF XY: 0.107 AC XY: 7927 AN XY: 74358

African (AFR) AF: 0.248 AC: 10297 AN: 41492

American (AMR) AF: 0.0565 AC: 864 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3466

East Asian (EAS) AF: 0.00484 AC: 25 AN: 5162

South Asian (SAS) AF: 0.0246 AC: 118 AN: 4796

European-Finnish (FIN) AF: 0.0748 AC: 793 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0596 AC: 4047 AN: 67952

Other (OTH) AF: 0.0986 AC: 208 AN: 2110

Alfa AF: 0.0714 Hom.: 913

Bravo AF: 0.114

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Smith-Magenis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.035
DANN	Benign	0.33
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4925112; hg19: chr17-17700573;