Genetic Variant NM_000964.4:c.470-58G>T (chr17-40351852-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000964.4(RARA):c.470-58G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,571,084 control chromosomes in the GnomAD database, including 1,414 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 0.028 ( 101 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1313 hom. )

Consequence

RARA
NM_000964.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.199

Publications

13 publications found

Variant links:

COSMIC-nc: COSV54189999

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:

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=-0.77).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4300/152254) while in subpopulation NFE AF = 0.0449 (3055/67988). AF 95% confidence interval is 0.0436. There are 101 homozygotes in GnomAd4. There are 2077 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4 link	c.470-58G>T		intron_variant	Intron 4 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10 link	c.470-58G>T		intron_variant	Intron 4 of 8	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4304

AN:

152136

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0439

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0450

Gnomad OTH

AF:

0.0182

GnomAD4 exome

AF:

0.0403

AC:

57111

AN:

1418830

Hom.:

1313

AF XY:

0.0399

AC XY:

28124

AN XY:

705554

show subpopulations

African (AFR)

AF:

0.00591

AC:

182

AN:

30806

American (AMR)

AF:

0.0105

AC:

337

AN:

32018

Ashkenazi Jewish (ASJ)

AF:

0.0384

AC:

934

AN:

24294

East Asian (EAS)

AF:

0.000154

AC:

AN:

39020

South Asian (SAS)

AF:

0.0245

AC:

1953

AN:

79812

European-Finnish (FIN)

AF:

0.0436

AC:

2237

AN:

51324

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

4806

European-Non Finnish (NFE)

AF:

0.0447

AC:

49084

AN:

1098198

Other (OTH)

AF:

0.0396

AC:

2321

AN:

58552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2991

5982

8972

11963

14954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1828

3656

5484

7312

9140

<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:

0.0282

AC:

4300

AN:

152254

Hom.:

101

Cov.:

AF XY:

0.0279

AC XY:

2077

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41574

American (AMR)

AF:

0.0120

AC:

184

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4826

European-Finnish (FIN)

AF:

0.0439

AC:

466

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0449

AC:

3055

AN:

67988

Other (OTH)

AF:

0.0180

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

224

447

671

894

1118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0347

Hom.:

Bravo

AF:

0.0243

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism

(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