Genetic Variant RARB:c.610-3786C>G (chr3-25576760-C-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_000965.5(RARB):c.610-3786C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 151,916 control chromosomes in the GnomAD database, including 11,213 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 0.38 ( 11213 hom., cov: 32)

Consequence

RARB
NM_000965.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.297

Publications

3 publications found

Variant links:

Genes affected

RARB (HGNC:9865): (retinoic acid receptor beta) This gene encodes retinoic acid receptor beta, a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators. This receptor localizes to the cytoplasm and to subnuclear compartments. It binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. It is thought that this protein limits growth of many cell types by regulating gene expression. The gene was first identified in a hepatocellular carcinoma where it flanks a hepatitis B virus integration site. Alternate promoter usage and differential splicing result in multiple transcript variants. [provided by RefSeq, Mar 2014]

RARB Gene-Disease associations (from GenCC):

microphthalmia, syndromic 12
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Baylor College of Medicine Research Center
Matthew-Wood syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RARB 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=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5 link	c.610-3786C>G		intron_variant	Intron 4 of 7	ENST00000330688.9	NP_000956.2	P10826-2F1D8S6Q86UC5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9 link	c.610-3786C>G		intron_variant	Intron 4 of 7	1	NM_000965.5	ENSP00000332296.4		P10826-2

Frequencies

GnomAD3 genomes

AF:

0.380

AC:

57701

AN:

151798

Hom.:

11190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.443

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.385

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.343

Gnomad OTH

AF:

0.359

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

GnomAD4 genome

AF:

0.380

AC:

57776

AN:

151916

Hom.:

11213

Cov.:

AF XY:

0.380

AC XY:

28198

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.444

AC:

18350

AN:

41370

American (AMR)

AF:

0.384

AC:

5874

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1149

AN:

3470

East Asian (EAS)

AF:

0.420

AC:

2162

AN:

5150

South Asian (SAS)

AF:

0.403

AC:

1941

AN:

4818

European-Finnish (FIN)

AF:

0.371

AC:

3912

AN:

10556

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.343

AC:

23304

AN:

67964

Other (OTH)

AF:

0.360

AC:

759

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1834

3669

5503

7338

9172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.361

Hom.:

1275

Bravo

AF:

0.388

Asia WGS

AF:

0.432

AC:

1506

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.18

(source)

DANN

Benign

0.45

PhyloP100

-0.30

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over