rs117995220

Variant names:

• chr17-17797460-G-T
• rs117995220
• NM_030665.4:c.4512G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_030665.4(RAI1):​c.4512G>T​(p.Leu1504Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,613,362 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1504L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (40 hom.)
• Consequence: RAI1 NM_030665.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.43
• Publications: 3 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=-0.5).
• BP6: Variant 17-17797460-G-T is Benign according to our data. Variant chr17-17797460-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00545 (830/152170) while in subpopulation AMR AF = 0.00895 (137/15302). AF 95% confidence interval is 0.00773. There are 3 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 830 AD gene.

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.4512G>T	p.Leu1504Leu	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.4512G>T	p.Leu1504Leu	synonymous	Exon 3 of 6	ENSP00000323074.4	Q7Z5J4-1
	RAI1	ENST00000918590.1		c.4512G>T	p.Leu1504Leu	synonymous	Exon 2 of 5	ENSP00000588649.1
	RAI1	ENST00000955422.1		c.4512G>T	p.Leu1504Leu	synonymous	Exon 3 of 6	ENSP00000625481.1

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 830 AN: 152052 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00574 AC: 1431 AN: 249324 AF XY: 0.00603

Gnomad AFR exome AF: 0.000888

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00806

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00662 AC: 9667 AN: 1461192 Hom.: 40 Cov.: 37 AF XY: 0.00647 AC XY: 4705 AN XY: 726886

African (AFR) AF: 0.000717 AC: 24 AN: 33470

American (AMR) AF: 0.00454 AC: 203 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 358 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86252

European-Finnish (FIN) AF: 0.00705 AC: 373 AN: 52910

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.00738 AC: 8207 AN: 1111892

Other (OTH) AF: 0.00682 AC: 412 AN: 60374

GnomAD4 genome AF: 0.00545 AC: 830 AN: 152170 Hom.: 3 Cov.: 33 AF XY: 0.00560 AC XY: 417 AN XY: 74410

African (AFR) AF: 0.00128 AC: 53 AN: 41528

American (AMR) AF: 0.00895 AC: 137 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00660 AC: 70 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00746 AC: 507 AN: 67974

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00741 Hom.: 5

Bravo AF: 0.00608

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00966

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Smith-Magenis syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		1.4
Mutation Taster		=94/6	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: rs117995220; hg19: chr17-17700774;