3-25174417-C-T

Variant names:

• chr3-25174417-C-T
• rs370145541
• NM_001290216.3:c.20C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001290216.3(RARB):​c.20C>T​(p.Ala7Val) variant causes a missense change. The variant allele was found at a frequency of 0.000377 in 1,352,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: RARB NM_001290216.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.75

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1353746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_001290216.3	c.20C>T	p.Ala7Val	missense_variant	Exon 4 of 11		NP_001277145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000383772.9	c.20C>T	p.Ala7Val	missense_variant	Exon 5 of 12	5		ENSP00000373282.5
RARB	ENST00000686715.1	c.20C>T	p.Ala7Val	missense_variant	Exon 5 of 12			ENSP00000510539.1
RARB	ENST00000687353.1	c.20C>T	p.Ala7Val	missense_variant	Exon 6 of 13			ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000262 AC: 60 AN: 229094 Hom.: 0 AF XY: 0.000253 AC XY: 32 AN XY: 126564

Gnomad AFR exome AF: 0.0000716

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000445

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000369 AC: 443 AN: 1199820 Hom.: 0 Cov.: 30 AF XY: 0.000392 AC XY: 233 AN XY: 594982

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.000295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.0000581

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74358

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000601

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000251 AC: 1

ExAC AF: 0.000208 AC: 24

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

RARB-related disorder Uncertain:1

Mar 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RARB c.20C>T variant is predicted to result in the amino acid substitution p.Ala7Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.17	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.39
Sift	Benign	0.031	D
Sift4G	Benign	0.79	T
MVP		0.54
ClinPred		0.033	T
GERP RS		5.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370145541; hg19: chr3-25215908;