rs9303286

Variant names:

• chr17-40344676-G-C
• rs9303286
• NM_000964.4:c.179-3640G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-40344676-G-C
• chr17-40344676-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000964.4(RARA):​c.179-3640G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,162 control chromosomes in the GnomAD database, including 5,726 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (5726 hom., cov: 32)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• Publications: 10 publications found

Genes affected

RARA (HGNC:9864): (retinoic acid receptor alpha) This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]

RARA Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• acute promyelocytic leukemia

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000964.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	NM_000964.4	MANE Select	c.179-3640G>C		intron	N/A	NP_000955.1
	RARA	NM_001145301.3		c.179-3640G>C		intron	N/A	NP_001138773.1
	RARA	NM_001024809.4		c.163+1809G>C		intron	N/A	NP_001019980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.179-3640G>C		intron	N/A	ENSP00000254066.5
	RARA	ENST00000394081.7	TSL:1	c.163+1809G>C		intron	N/A	ENSP00000377643.3
	RARA	ENST00000425707.7	TSL:1	c.179-7234G>C		intron	N/A	ENSP00000389993.3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33711 AN: 152044 Hom.: 5690 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0942

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.180

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.222 AC: 33811 AN: 152162 Hom.: 5726 Cov.: 32 AF XY: 0.222 AC XY: 16485 AN XY: 74378

African (AFR) AF: 0.472 AC: 19569 AN: 41478

American (AMR) AF: 0.154 AC: 2363 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 327 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1913 AN: 5172

South Asian (SAS) AF: 0.103 AC: 495 AN: 4820

European-Finnish (FIN) AF: 0.128 AC: 1355 AN: 10602

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7183 AN: 68006

Other (OTH) AF: 0.180 AC: 380 AN: 2112

Alfa AF: 0.0456 Hom.: 41

Bravo AF: 0.238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.56
PhyloP100		0.27
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: rs9303286; hg19: chr17-38500928; COSMIC: COSV54190065;