3-25580574-T-C

Variant names:

• chr3-25580574-T-C
• rs869025222
• NM_000965.5:c.638T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP2 PP5_Very_Strong

The NM_000965.5(RARB):​c.638T>C​(p.Leu213Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000814431: Experimental studies have shown that this missense change results in a protein with increased transcriptional activity relative to wildtype, consistent with the known gain-of-function mechanism underlying this disease (PMID:27120018)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARB NM_000965.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.28
• 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: 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000814431: Experimental studies have shown that this missense change results in a protein with increased transcriptional activity relative to wildtype, consistent with the known gain-of-function mechanism underlying this disease (PMID: 27120018).; SCV002770006: Published functional studies demonstrated increased transcriptional activity indicating a gain-of-function (Srour et al., 2016)
• 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
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 3-25580574-T-C is Pathogenic according to our data. Variant chr3-25580574-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.638T>C	p.Leu213Pro	missense	Exon 5 of 8	NP_000956.2
	RARB	NM_001290216.3		c.659T>C	p.Leu220Pro	missense	Exon 8 of 11	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.509T>C	p.Leu170Pro	missense	Exon 5 of 8	NP_001277229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000330688.9	TSL:1 MANE Select	c.638T>C	p.Leu213Pro	missense	Exon 5 of 8	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.302T>C	p.Leu101Pro	missense	Exon 5 of 8	ENSP00000398840.2	P10826-3
	RARB	ENST00000458646.2	TSL:1	c.302T>C	p.Leu101Pro	missense	Exon 5 of 8	ENSP00000391391.1	P10826-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Microphthalmia, syndromic 12 (3)
1	-	-	Intellectual disability, autosomal dominant 48 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.80	T
PhyloP100		6.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Vest4		0.91
MutPred		0.54		Loss of stability (P = 8e-04)
MVP		0.88
MPC		2.4
ClinPred		0.98	D
GERP RS		4.0
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs869025222; hg19: chr3-25622065;