dbSNP rs369374366: CRB3:p.Thr89Arg (chr19-6466575-C-G) – 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.266C>G(p.Thr89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,314 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T89M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CRB3
NM_139161.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

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.266C>G	p.Thr89Arg	missense_variant	Exon 4 of 4	ENST00000600229.6	NP_631900.1	Q9BUF7-1
CRB3	NM_174881.4 link	c.266C>G	p.Thr89Arg	missense_variant	Exon 4 of 5		NP_777377.1	Q9BUF7-2
CRB3	NM_174882.3 link	c.266C>G	p.Thr89Arg	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.266C>G	p.Thr89Arg	missense_variant	Exon 4 of 4	2	NM_139161.5	ENSP00000472010.1	Q9BUF7-1
CRB3	ENST00000356762.7 link	c.266C>G	p.Thr89Arg	missense_variant	Exon 4 of 5	1		ENSP00000349204.2	Q9BUF7-2
CRB3	ENST00000308243.7 link	c.266C>G	p.Thr89Arg	missense_variant	Exon 3 of 3	2		ENSP00000310123.6	Q9BUF7-1
CRB3	ENST00000598494.5 link	c.266C>G	p.Thr89Arg	missense_variant	Exon 4 of 4	2		ENSP00000469707.1	Q9BUF7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.86

.;.;D;T

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.0

M;M;M;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.3

.;.;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.56

MutPred

0.28

Loss of phosphorylation at T89 (P = 0.0252);Loss of phosphorylation at T89 (P = 0.0252);Loss of phosphorylation at T89 (P = 0.0252);Loss of phosphorylation at T89 (P = 0.0252);

MVP

0.23

MPC

1.2

ClinPred

0.99

GERP RS

5.0

Varity_R

0.64

gMVP

0.76

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over