Genetic Variant CRB3:p.Ile61Asn (chr19-6466491-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139161.5(CRB3):c.182T>A(p.Ile61Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CRB3
NM_139161.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.239

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26085675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB3	NM_139161.5 link	c.182T>A	p.Ile61Asn	missense_variant	Exon 4 of 4	ENST00000600229.6	NP_631900.1	Q9BUF7-1
CRB3	NM_174881.4 link	c.182T>A	p.Ile61Asn	missense_variant	Exon 4 of 5		NP_777377.1	Q9BUF7-2
CRB3	NM_174882.3 link	c.182T>A	p.Ile61Asn	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.182T>A	p.Ile61Asn	missense_variant	Exon 4 of 4	2	NM_139161.5	ENSP00000472010.1	Q9BUF7-1
CRB3	ENST00000356762.7 link	c.182T>A	p.Ile61Asn	missense_variant	Exon 4 of 5	1		ENSP00000349204.2	Q9BUF7-2
CRB3	ENST00000308243.7 link	c.182T>A	p.Ile61Asn	missense_variant	Exon 3 of 3	2		ENSP00000310123.6	Q9BUF7-1
CRB3	ENST00000598494.5 link	c.182T>A	p.Ile61Asn	missense_variant	Exon 4 of 4	2		ENSP00000469707.1	Q9BUF7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249986

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

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.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182T>A (p.I61N) alteration is located in exon 4 (coding exon 3) of the CRB3 gene. This alteration results from a T to A substitution at nucleotide position 182, causing the isoleucine (I) at amino acid position 61 to be replaced by an asparagine (N). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.76

.;.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.9

M;M;M;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.4

.;.;D;D

REVEL

Benign

0.077

Sift

Uncertain

0.021

.;.;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

0.93

P;P;P;P

Vest4

0.62

MutPred

0.41

Gain of catalytic residue at I61 (P = 0.0057);Gain of catalytic residue at I61 (P = 0.0057);Gain of catalytic residue at I61 (P = 0.0057);Gain of catalytic residue at I61 (P = 0.0057);

MVP

0.20

MPC

1.5

ClinPred

0.88

GERP RS

1.2

Varity_R

0.17

gMVP

0.81

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

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