Genetic Variant PRRG1:p.Ile93Phe (chrX-37453241-A-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001142395.2(PRRG1):c.277A>T(p.Ile93Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,640 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I93V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

PRRG1
NM_001142395.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.276

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32257867).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2 link	c.277A>T	p.Ile93Phe	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1	O14668-1Q8NEK6
PRRG1	NM_000950.3 link	c.277A>T	p.Ile93Phe	missense_variant	Exon 5 of 5		NP_000941.1	O14668-1Q8NEK6
PRRG1	NM_001173489.2 link	c.277A>T	p.Ile93Phe	missense_variant	Exon 5 of 5		NP_001166960.1	O14668-1
PRRG1	NM_001173490.2 link	c.277A>T	p.Ile93Phe	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.277A>T	p.Ile93Phe	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4		O14668-1
ENSG00000250349	ENST00000465127.1 link	c.171+27241A>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097640

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26390

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841598

Other (OTH)

AF:

0.00

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.044

T;T;T;T;T;T

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.72

.;T;.;T;T;.

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.32

T;T;T;T;T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

1.2

L;.;L;L;.;L

PhyloP100

0.28

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D;T;D

Polyphen

0.84

P;.;P;P;.;P

Vest4

0.18

MutPred

0.56

Loss of catalytic residue at I93 (P = 0.063);Loss of catalytic residue at I93 (P = 0.063);Loss of catalytic residue at I93 (P = 0.063);Loss of catalytic residue at I93 (P = 0.063);Loss of catalytic residue at I93 (P = 0.063);Loss of catalytic residue at I93 (P = 0.063);

MVP

0.60

MPC

0.41

ClinPred

0.78

GERP RS

3.7

Varity_R

0.35

gMVP

0.70

Mutation Taster

=73/27

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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X-37453241-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over