6-41784225-C-T

Variant summary

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

The NM_013397.6(PRICKLE4):​c.227C>T​(p.Pro76Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,610,674 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: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PRICKLE4
NM_013397.6 missense

Scores

2
13
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46
Variant links:
Genes affected
PRICKLE4 (HGNC:16805): (prickle planar cell polarity protein 4) C6ORF49 is a member of the LIM domain protein family (Teufel et al., 2005 [PubMed 15702247]).[supplied by OMIM, Mar 2008]
FRS3 (HGNC:16970): (fibroblast growth factor receptor substrate 3) This gene encodes a substrate for the fibroblast growth factor receptor. The encoded protein is found in the peripheral plasma membrane and links fibroblast growth factor receptor stimulation to activators of Ras. The encoded protein down-regulates extracellular regulated kinase 2 through direct binding. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

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
PRICKLE4NM_013397.6 linkc.227C>T p.Pro76Leu missense_variant Exon 4 of 8 ENST00000458694.6 NP_037529.3 Q2TBC4-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRICKLE4ENST00000458694.6 linkc.227C>T p.Pro76Leu missense_variant Exon 4 of 8 5 NM_013397.6 ENSP00000404911.1 Q2TBC4-3
ENSG00000124593ENST00000335515.10 linkn.227C>T non_coding_transcript_exon_variant Exon 3 of 9 2 ENSP00000335185.6

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000362
AC:
9
AN:
248646
Hom.:
0
AF XY:
0.0000372
AC XY:
5
AN XY:
134462
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000295
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1458488
Hom.:
0
Cov.:
30
AF XY:
0.0000331
AC XY:
24
AN XY:
725658
show subpopulations
Gnomad4 AFR exome
AF:
0.0000900
Gnomad4 AMR exome
AF:
0.0000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.227C>T (p.P76L) alteration is located in exon 4 (coding exon 2) of the PRICKLE4 gene. This alteration results from a C to T substitution at nucleotide position 227, causing the proline (P) at amino acid position 76 to be replaced by a leucine (L). 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
Benign
0.19
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.068
.;T;.;.;T
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.92
D;D;.;D;.
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.66
D;D;D;D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.5
.;M;.;M;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-9.7
D;.;D;D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0070
D;.;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.54
MVP
0.86
MPC
1.1
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.31

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: rs752836843; hg19: chr6-41751963; COSMIC: COSV59254307; COSMIC: COSV59254307; API