dbSNP rs482284: RARA:c.179-327A>G (chr17-40347989-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000964.4(RARA):c.179-327A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 231,096 control chromosomes in the GnomAD database, including 44,151 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 0.55 ( 26825 hom., cov: 32)

Exomes 𝑓: 0.65 ( 17326 hom. )

Consequence

RARA
NM_000964.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

Publications

14 publications found

Variant links:

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

RARA links:

ENSG00000278918 (HGNC:):

ENSG00000278918 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4 link	c.179-327A>G		intron_variant	Intron 2 of 8	ENST00000254066.10	NP_000955.1	P10276-1Q6I9R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10 link	c.179-327A>G		intron_variant	Intron 2 of 8	1	NM_000964.4	ENSP00000254066.5		P10276-1

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

84154

AN:

151876

Hom.:

26827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.527

Gnomad AMR

AF:

0.689

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.701

Gnomad FIN

AF:

0.658

Gnomad MID

AF:

0.587

Gnomad NFE

AF:

0.699

Gnomad OTH

AF:

0.603

GnomAD4 exome

AF:

0.648

AC:

51226

AN:

79102

Hom.:

17326

AF XY:

0.652

AC XY:

25993

AN XY:

39848

show subpopulations

African (AFR)

AF:

0.230

AC:

654

AN:

2840

American (AMR)

AF:

0.700

AC:

1462

AN:

2088

Ashkenazi Jewish (ASJ)

AF:

0.670

AC:

2315

AN:

3454

East Asian (EAS)

AF:

0.403

AC:

2786

AN:

6906

South Asian (SAS)

AF:

0.685

AC:

1260

AN:

1840

European-Finnish (FIN)

AF:

0.666

AC:

3082

AN:

4628

Middle Eastern (MID)

AF:

0.657

AC:

272

AN:

414

European-Non Finnish (NFE)

AF:

0.698

AC:

35782

AN:

51258

Other (OTH)

AF:

0.637

AC:

3613

AN:

5674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

829

1658

2488

3317

4146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.554

AC:

84143

AN:

151994

Hom.:

26825

Cov.:

AF XY:

0.557

AC XY:

41368

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.215

AC:

8913

AN:

41432

American (AMR)

AF:

0.689

AC:

10534

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2368

AN:

3468

East Asian (EAS)

AF:

0.494

AC:

2547

AN:

5152

South Asian (SAS)

AF:

0.701

AC:

3382

AN:

4822

European-Finnish (FIN)

AF:

0.658

AC:

6939

AN:

10548

Middle Eastern (MID)

AF:

0.586

AC:

170

AN:

290

European-Non Finnish (NFE)

AF:

0.699

AC:

47547

AN:

67976

Other (OTH)

AF:

0.599

AC:

1263

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1621

3242

4862

6483

8104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.641

Hom.:

43198

Bravo

AF:

0.540

Asia WGS

AF:

0.537

AC:

1867

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.94

(source)

DANN

Benign

0.66

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over