Genetic Variant CRB3:p.Arg94Trp (chr19-6466589-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139161.5(CRB3):c.280C>T(p.Arg94Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,609,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CRB3
NM_139161.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Variant links:

Genes affected

CRB3 (HGNC:20237): (crumbs cell polarity complex component 3) This gene encodes a member of the Crumbs family of proteins. This gene is widely expressed in epithelial tissues where the encoded protein isoforms play various roles such as the control of cytokinesis and ciliogenesis or the formation of tight junctions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

CRB3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB3	NM_139161.5 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 4	ENST00000600229.6	NP_631900.1	Q9BUF7-1
CRB3	NM_174881.4 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 5		NP_777377.1	Q9BUF7-2
CRB3	NM_174882.3 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 4		NP_777378.1	Q9BUF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRB3	ENST00000600229.6 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 4	2	NM_139161.5	ENSP00000472010.1	Q9BUF7-1
CRB3	ENST00000356762.7 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 5	1		ENSP00000349204.2	Q9BUF7-2
CRB3	ENST00000308243.7 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 3 of 3	2		ENSP00000310123.6	Q9BUF7-1
CRB3	ENST00000598494.5 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 4	2		ENSP00000469707.1	Q9BUF7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000405

AC:

AN:

247172

Hom.:

AF XY:

0.0000522

AC XY:

AN XY:

134034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1456870

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

724956

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280C>T (p.R94W) alteration is located in exon 4 (coding exon 3) of the CRB3 gene. This alteration results from a C to T substitution at nucleotide position 280, causing the arginine (R) at amino acid position 94 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;T;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.88

.;.;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.61

D;D;D;D

MetaSVM

Uncertain

-0.074

MutationAssessor

Uncertain

2.8

M;M;M;M

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.7

.;.;D;D

REVEL

Benign

0.19

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.67

MutPred

0.25

Loss of phosphorylation at S97 (P = 0.0621);Loss of phosphorylation at S97 (P = 0.0621);Loss of phosphorylation at S97 (P = 0.0621);Loss of phosphorylation at S97 (P = 0.0621);

MVP

0.53

MPC

1.1

ClinPred

0.93

GERP RS

5.0

Varity_R

0.59

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over