rs397518483

Positions:

• chr3-25596428-C-A
• chr3-25596428-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_000965.5(RARB):​c.1159C>A​(p.Arg387Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R387C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RARB NM_000965.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.17

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-25596428-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RARB. . Gene score misZ 2.8661 (greater than the threshold 3.09). Trascript score misZ 3.1257 (greater than threshold 3.09). GenCC has associacion of gene with microphthalmia, syndromic 12, Matthew-Wood syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 3-25596428-C-A is Pathogenic according to our data. Variant chr3-25596428-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 88763.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARB	NM_000965.5	c.1159C>A	p.Arg387Ser	missense_variant	8/8	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.1159C>A	p.Arg387Ser	missense_variant	8/8	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457870 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microphthalmia, syndromic 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0070	D;T;D;T
Vest4		0.78, 0.87
MutPred		0.53		Loss of MoRF binding (P = 0.0143);.;.;.;
MVP		0.98
MPC		2.0
ClinPred		0.98	D
GERP RS		5.8
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs397518483; hg19: chr3-25637919;