chr3-25174527-C-G

Variant names:

• chr3-25174527-C-G
• rs759370316
• NM_001290216.3:c.130C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001290216.3(RARB):​c.130C>G​(p.Leu44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,352,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RARB NM_001290216.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Baylor College of Medicine Research Center, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Matthew-Wood syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.8661 (below the threshold of 3.09). Trascript score misZ: 2.6333 (below the threshold of 3.09). GenCC associations: The gene is linked to microphthalmia, syndromic 12, Matthew-Wood syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13022444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	NM_001290216.3		c.130C>G	p.Leu44Val	missense	Exon 4 of 11	NP_001277145.1	P10826-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000383772.9	TSL:5	c.130C>G	p.Leu44Val	missense	Exon 5 of 12	ENSP00000373282.5	P10826-1
	RARB	ENST00000686715.1		c.130C>G	p.Leu44Val	missense	Exon 5 of 12	ENSP00000510539.1	P10826-1
	RARB	ENST00000687353.1		c.130C>G	p.Leu44Val	missense	Exon 6 of 13	ENSP00000508588.1	P10826-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 229300 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000284

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 18 AN: 1199824 Hom.: 0 Cov.: 30 AF XY: 0.0000235 AC XY: 14 AN XY: 594976

African (AFR) AF: 0.00 AC: 0 AN: 26296

American (AMR) AF: 0.00 AC: 0 AN: 37286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16896

East Asian (EAS) AF: 0.00 AC: 0 AN: 16800

South Asian (SAS) AF: 0.00 AC: 0 AN: 83224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4472

European-Non Finnish (NFE) AF: 0.0000189 AC: 18 AN: 953748

Other (OTH) AF: 0.00 AC: 0 AN: 43910

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000482 AC: 2 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	RARB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.41	T
PhyloP100		2.3
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.52	T
MVP		0.67
ClinPred		0.17	T
GERP RS		5.0
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs759370316; hg19: chr3-25216018;