rs12051734

Variant names:

• chr17-40337898-C-T
• rs12051734
• NM_000964.4:c.178+6502C>T

Variant summary

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

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_000964.4(RARA):​c.178+6502C>T 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 152,074 control chromosomes in the GnomAD database, including 5,694 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 (5694 hom., cov: 33)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.619
• Publications: 5 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=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.178+6502C>T		intron_variant	Intron 2 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.178+6502C>T		intron_variant	Intron 2 of 8	1	NM_000964.4	ENSP00000254066.5
RARA	ENST00000425707.7	c.178+6502C>T		intron_variant	Intron 2 of 6	1		ENSP00000389993.3
RARA	ENST00000394089.6	c.178+6502C>T		intron_variant	Intron 2 of 8	2		ENSP00000377649.2
RARA	ENST00000577646.5	c.178+6502C>T		intron_variant	Intron 3 of 3	5		ENSP00000464287.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33606 AN: 151954 Hom.: 5659 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0907

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.0999

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.105

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: 33704 AN: 152074 Hom.: 5694 Cov.: 33 AF XY: 0.221 AC XY: 16427 AN XY: 74354

African (AFR) AF: 0.471 AC: 19522 AN: 41412

American (AMR) AF: 0.155 AC: 2368 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 315 AN: 3472

East Asian (EAS) AF: 0.364 AC: 1884 AN: 5172

South Asian (SAS) AF: 0.101 AC: 487 AN: 4830

European-Finnish (FIN) AF: 0.128 AC: 1359 AN: 10612

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

European-Non Finnish (NFE) AF: 0.105 AC: 7165 AN: 67978

Other (OTH) AF: 0.179 AC: 379 AN: 2114

Alfa AF: 0.149 Hom.: 411

Bravo AF: 0.237

Asia WGS AF: 0.234 AC: 812 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.84
PhyloP100		-0.62
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: rs12051734; hg19: chr17-38494150; COSMIC: COSV54190036;