19-6466976-C-T

Variant summary

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

The NM_174881.4(CRB3):​c.326C>T​(p.Ala109Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CRB3
NM_174881.4 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.107
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]
DENND1C (HGNC:26225): (DENN domain containing 1C) The protein encoded by this gene functions as a guanine nucleotide exchange factor for the early endosomal small GTPase RAB35, which regulates endosomal membrane trafficking and is involved in actin polymerization. The encoded protein activates RAB35 by promoting the exchange of RAB35-bound GDP for GTP. This gene may play a role in linking RAB35 activation with the clathrin machinery. [provided by RefSeq, May 2017]

Genome browser will be placed here

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=0.07327551).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRB3NM_139161.5 linkc.*304C>T 3_prime_UTR_variant Exon 4 of 4 ENST00000600229.6 NP_631900.1 Q9BUF7-1
DENND1CNM_024898.4 linkc.*528G>A downstream_gene_variant ENST00000381480.7 NP_079174.2 Q8IV53-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CRB3ENST00000600229.6 linkc.*304C>T 3_prime_UTR_variant Exon 4 of 4 2 NM_139161.5 ENSP00000472010.1 Q9BUF7-1
DENND1CENST00000381480.7 linkc.*528G>A downstream_gene_variant 1 NM_024898.4 ENSP00000370889.1 Q8IV53-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152072
Hom.:
0
Cov.:
31
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251368
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.00000274
AC:
4
AN:
1461850
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 16, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.326C>T (p.A109V) alteration is located in exon 5 (coding exon 4) of the CRB3 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the alanine (A) at amino acid position 109 to be replaced by a valine (V). 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
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
17
DANN
Benign
0.97
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.073
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.69
N
REVEL
Benign
0.082
Sift
Benign
0.095
T
Sift4G
Benign
0.31
T
Polyphen
0.077
B
Vest4
0.15
MutPred
0.086
Gain of methylation at K114 (P = 0.1062);
MVP
0.095
MPC
0.37
ClinPred
0.56
D
GERP RS
2.5
gMVP
0.63

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.

Other links and lift over

dbSNP: rs369789348; hg19: chr19-6466987; API