chrX-49177028-G-A

Position:

• chrX-49177028-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006150.5(PRICKLE3):​c.1130C>T​(p.Pro377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,207,814 control chromosomes in the GnomAD database, including 1 homozygotes. There are 142 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00036 (1 hom. 131 hem.)
• Consequence: PRICKLE3 NM_006150.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.807

Genes affected

PRICKLE3 (HGNC:6645): (prickle planar cell polarity protein 3) LIM domain only 6 is a three LIM domain-containing protein. The LIM domain is a cysteine-rich sequence motif that binds zinc atoms to form a specific protein-binding interface for protein-protein interactions. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039325178).
• BP6: Variant X-49177028-G-A is Benign according to our data. Variant chrX-49177028-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2507491.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE3	NM_006150.5	c.1130C>T	p.Pro377Leu	missense_variant	8/9	ENST00000599218.6
PRICKLE3	NM_001307979.2	c.926C>T	p.Pro309Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE3	ENST00000599218.6	c.1130C>T	p.Pro377Leu	missense_variant	8/9	1	NM_006150.5	P3
PRICKLE3	ENST00000453382.5	c.926C>T	p.Pro309Leu	missense_variant	7/8	5		A2
PRICKLE3	ENST00000540849.5	c.*592C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 27 AN: 112579 Hom.: 0 Cov.: 23 AF XY: 0.000317 AC XY: 11 AN XY: 34751

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000372

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.000656

GnomAD3 exomes AF: 0.000428 AC: 74 AN: 172715 Hom.: 0 AF XY: 0.000352 AC XY: 21 AN XY: 59705

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000599

Gnomad ASJ exome AF: 0.000820

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000673

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000364 AC: 399 AN: 1095180 Hom.: 1 Cov.: 31 AF XY: 0.000363 AC XY: 131 AN XY: 361008

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000429

Gnomad4 ASJ exome AF: 0.000673

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.0000249

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.000523

GnomAD4 genome AF: 0.000240 AC: 27 AN: 112634 Hom.: 0 Cov.: 23 AF XY: 0.000316 AC XY: 11 AN XY: 34816

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.000372

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.000648

Alfa AF: 0.000234 Hom.: 2

Bravo AF: 0.000329

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.000363 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.1130C>T (p.P377L) alteration is located in exon 8 (coding exon 8) of the PRICKLE3 gene. This alteration results from a C to T substitution at nucleotide position 1130, causing the proline (P) at amino acid position 377 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PRICKLE3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.048	T;.
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.014	D;T
Polyphen		0.18	B;.
Vest4		0.10
MVP		0.23
ClinPred		0.021	T
GERP RS		2.6
Varity_R		0.044
gMVP		0.20

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

Other links and lift over

dbSNP: rs146977278; hg19: chrX-49033377;