chrX-37453365-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142395.2(PRRG1):c.401C>A(p.Pro134Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,206,725 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P134R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000022 ( 0 hom. 9 hem. )

Consequence

PRRG1
NM_001142395.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59

Publications

2 publications found

Variant links:

Genes affected

PRRG1 (HGNC:9469): (proline rich and Gla domain 1) This gene encodes a vitamin K-dependent, gamma-carboxyglutamic acid (Gla)-containing, single-pass transmembrane protein. This protein contains a Gla domain at the N-terminus, preceded by a propeptide sequence required for post-translational gamma-carboxylation of specific glutamic acid residues by a vitamin K-dependent gamma-carboxylase. The C-terminus is proline-rich containing PPXY and PXXP motifs found in a variety of signaling and cytoskeletal proteins. This gene is highly expressed in the spinal cord. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2010]

PRRG1 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21185464).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2 link	c.401C>A	p.Pro134Gln	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1	O14668-1Q8NEK6
PRRG1	NM_000950.3 link	c.401C>A	p.Pro134Gln	missense_variant	Exon 5 of 5		NP_000941.1	O14668-1Q8NEK6
PRRG1	NM_001173489.2 link	c.401C>A	p.Pro134Gln	missense_variant	Exon 5 of 5		NP_001166960.1	O14668-1
PRRG1	NM_001173490.2 link	c.401C>A	p.Pro134Gln	missense_variant	Exon 4 of 4		NP_001166961.1	O14668-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRG1	ENST00000378628.9 link	c.401C>A	p.Pro134Gln	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4		O14668-1
ENSG00000250349	ENST00000465127.1 link	c.171+27365C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000549

AC:

AN:

109248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000134

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:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183353

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1097477

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362909

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26391

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

841434

Other (OTH)

AF:

0.00

AC:

AN:

46077

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000549

AC:

AN:

109248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31524

show subpopulations

African (AFR)

AF:

0.000134

AC:

AN:

29914

American (AMR)

AF:

0.00

AC:

AN:

10132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2613

East Asian (EAS)

AF:

0.00

AC:

AN:

3499

South Asian (SAS)

AF:

0.00

AC:

AN:

2430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

52504

Other (OTH)

AF:

0.00

AC:

AN:

1450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.401C>A (p.P134Q) alteration is located in exon 5 (coding exon 3) of the PRRG1 gene. This alteration results from a C to A substitution at nucleotide position 401, causing the proline (P) at amino acid position 134 to be replaced by a glutamine (Q). 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

0.075

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.034

T;T;T;T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.62

.;T;.;T;.

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.4

L;.;L;L;L

PhyloP100

2.6

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.12

N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.19

T;D;T;T;T

Sift4G

Uncertain

0.036

D;D;D;D;D

Polyphen

0.0

B;.;B;B;B

Vest4

0.22

MutPred

0.36

Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);

MVP

0.46

MPC

0.26

ClinPred

0.12

GERP RS

5.3

Varity_R

0.087

gMVP

0.47

Mutation Taster

=100/0

polymorphism

(source)

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

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chrX-37453365-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over