X-49176971-G-A

Position:

• chrX-49176971-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006150.5(PRICKLE3):​c.1187C>T​(p.Ala396Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: PRICKLE3 NM_006150.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14501294).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE3	NM_006150.5	c.1187C>T	p.Ala396Val	missense_variant	8/9	ENST00000599218.6
PRICKLE3	NM_001307979.2	c.983C>T	p.Ala328Val	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE3	ENST00000599218.6	c.1187C>T	p.Ala396Val	missense_variant	8/9	1	NM_006150.5	P3
PRICKLE3	ENST00000453382.5	c.983C>T	p.Ala328Val	missense_variant	7/8	5		A2
PRICKLE3	ENST00000540849.5	c.*649C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097238 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362760

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.1187C>T (p.A396V) 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 1187, causing the alanine (A) at amino acid position 396 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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.37	T;T
Polyphen		0.94	P;.
Vest4		0.15
MutPred		0.24		Gain of helix (P = 0.0093);.;
MVP		0.33
ClinPred		0.27	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201045789; hg19: chrX-49033320;