rs2067964

Variant names:

• chr3-25461378-T-G
• rs2067964
• NM_000965.5:c.306+37T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000965.5(RARB):​c.306+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,604,214 control chromosomes in the GnomAD database, including 11,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1374 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9770 hom.)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-25461378-T-G is Benign according to our data. Variant chr3-25461378-T-G is described in ClinVar as Benign. ClinVar VariationId is 1277051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.306+37T>G		intron_variant	Intron 2 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.306+37T>G		intron_variant	Intron 2 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19819 AN: 152082 Hom.: 1371 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0927

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.114 AC: 27616 AN: 242730 AF XY: 0.114

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0640

Gnomad ASJ exome AF: 0.0930

Gnomad EAS exome AF: 0.0982

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.113 AC: 164127 AN: 1452012 Hom.: 9770 Cov.: 32 AF XY: 0.113 AC XY: 81813 AN XY: 721544

African (AFR) AF: 0.188 AC: 6267 AN: 33270

American (AMR) AF: 0.0663 AC: 2895 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 2265 AN: 25416

East Asian (EAS) AF: 0.131 AC: 5167 AN: 39532

South Asian (SAS) AF: 0.132 AC: 11181 AN: 84470

European-Finnish (FIN) AF: 0.129 AC: 6848 AN: 53070

Middle Eastern (MID) AF: 0.112 AC: 641 AN: 5720

European-Non Finnish (NFE) AF: 0.110 AC: 121892 AN: 1106908

Other (OTH) AF: 0.116 AC: 6971 AN: 59990

GnomAD4 genome AF: 0.130 AC: 19848 AN: 152202 Hom.: 1374 Cov.: 32 AF XY: 0.132 AC XY: 9798 AN XY: 74404

African (AFR) AF: 0.182 AC: 7571 AN: 41518

American (AMR) AF: 0.0928 AC: 1419 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 296 AN: 3470

East Asian (EAS) AF: 0.118 AC: 608 AN: 5162

South Asian (SAS) AF: 0.139 AC: 672 AN: 4820

European-Finnish (FIN) AF: 0.137 AC: 1454 AN: 10610

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7496 AN: 68002

Other (OTH) AF: 0.126 AC: 266 AN: 2116

Alfa AF: 0.121 Hom.: 1763

Bravo AF: 0.129

Asia WGS AF: 0.145 AC: 502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.71
DANN	Benign	0.41
PhyloP100		-0.21
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: rs2067964; hg19: chr3-25502869;