17-40324405-C-G

Variant names:

• chr17-40324405-C-G
• rs12946680
• NM_000964.4:c.-362-6452C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	NM_000964.4	MANE Select	c.-362-6452C>G		intron	N/A	NP_000955.1	P10276-1
	RARA	NM_001145301.3		c.-363+5957C>G		intron	N/A	NP_001138773.1	Q6I9R7
	RARA	NM_001145302.3		c.-363+5957C>G		intron	N/A	NP_001138774.1	P10276-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.-362-6452C>G		intron	N/A	ENSP00000254066.5	P10276-1
	RARA	ENST00000425707.7	TSL:1	c.-363+5957C>G		intron	N/A	ENSP00000389993.3	P10276-3
	RARA	ENST00000857085.1		c.-558C>G		5_prime_UTR	Exon 1 of 9	ENSP00000527144.1

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

African (AFR) AF: 0.486 AC: 20095 AN: 41316

American (AMR) AF: 0.174 AC: 2653 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 331 AN: 3472

East Asian (EAS) AF: 0.350 AC: 1799 AN: 5134

South Asian (SAS) AF: 0.105 AC: 503 AN: 4806

European-Finnish (FIN) AF: 0.144 AC: 1520 AN: 10562

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8705 AN: 67954

Other (OTH) AF: 0.196 AC: 414 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.0
DANN	Benign	0.68
PhyloP100		-0.17
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: rs12946680; hg19: chr17-38480657;