3-25580574-TG-CT

Variant names:

• chr3-25580574-TG-CT
• NM_000965.5:c.638_639delTGinsCT
• RARB p.Leu213Pro

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Very_Strong PM1 PP2

The NM_000965.5(RARB):​c.638_639delTGinsCT​(p.Leu213Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARB NM_000965.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Baylor College of Medicine Research Center, ClinGen
• Matthew-Wood syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_000965.5 (RARB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000965.5
• PP2: Missense variant in the RARB gene, where missense mutations are typically associated with disease (based on misZ statistic). 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: 3.1257 (above the threshold of 3.09). GenCC associations: The gene is linked to microphthalmia, syndromic 12, Matthew-Wood syndrome.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000965.5. 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_000965.5	MANE Select	c.638_639delTGinsCT	p.Leu213Pro	missense	N/A	NP_000956.2
	RARB	NM_001290216.3		c.659_660delTGinsCT	p.Leu220Pro	missense	N/A	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.509_510delTGinsCT	p.Leu170Pro	missense	N/A	NP_001277229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000330688.9	TSL:1 MANE Select	c.638_639delTGinsCT	p.Leu213Pro	missense	N/A	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.302_303delTGinsCT	p.Leu101Pro	missense	N/A	ENSP00000398840.2	P10826-3
	RARB	ENST00000458646.2	TSL:1	c.302_303delTGinsCT	p.Leu101Pro	missense	N/A	ENSP00000391391.1	P10826-3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-25622065;