rs1057520141

Variant names:

• chr12-42460268-T-A
• rs1057520141
• NM_153026.3:c.2037A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-42460268-T-A
• chr12-42460268-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153026.3(PRICKLE1):​c.2037A>T​(p.Arg679Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.961
• Publications: 0 publications found

Genes affected

PRICKLE1 (HGNC:17019): (prickle planar cell polarity protein 1) This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]

PRICKLE1 Gene-Disease associations (from GenCC):

• epilepsy, progressive myoclonic, 1B

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000257225 (HGNC:58444):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29378664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.2037A>T	p.Arg679Ser	missense_variant	Exon 8 of 8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.2037A>T	p.Arg679Ser	missense_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.24	N
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;.;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M;M;M;M
PhyloP100		-0.96
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;.;D;.;D;.;.;D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;D;.;D;.;.;D;.;D
Sift4G	Uncertain	0.0060	D;.;D;.;D;.;.;D;.;D
Polyphen		0.91	P;P;P;P;P;P;P;P;P;P
Vest4		0.65
MutPred		0.39		Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);Gain of phosphorylation at R679 (P = 2e-04);
MVP		0.60
MPC		1.2
ClinPred		0.99	D
GERP RS		-4.4
Varity_R		0.74
gMVP		0.50
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1057520141; hg19: chr12-42854070;