17-40324405-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000964.4(RARA):c.-362-6452C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,834 control chromosomes in the GnomAD database, including 6,218 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 0.24 (6218 hom., cov: 31)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARA	NM_000964.4	c.-362-6452C>G		intron_variant		ENST00000254066.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARA	ENST00000254066.10	c.-362-6452C>G		intron_variant		1	NM_000964.4	P4

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36149 AN: 151716 Hom.: 6181 Cov.: 31

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.239 AC: 36249 AN: 151834 Hom.: 6218 Cov.: 31 AF XY: 0.238 AC XY: 17643 AN XY: 74204

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0953

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.196

Alfa AF: 0.0541 Hom.: 50

Bravo AF: 0.255

Asia WGS AF: 0.234 AC: 815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	8.0
Dann	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs12946680; hg19: chr17-38480657;