X-37453401-C-T

Variant names:

• chrX-37453401-C-T
• rs1271071931
• NM_001142395.2:c.437C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001142395.2(PRRG1):​c.437C>T​(p.Pro146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

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]

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.437C>T	p.Pro146Leu	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1
PRRG1	NM_000950.3	c.437C>T	p.Pro146Leu	missense_variant	Exon 5 of 5		NP_000941.1
PRRG1	NM_001173489.2	c.437C>T	p.Pro146Leu	missense_variant	Exon 5 of 5		NP_001166960.1
PRRG1	NM_001173490.2	c.437C>T	p.Pro146Leu	missense_variant	Exon 4 of 4		NP_001166961.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRG1	ENST00000378628.9	c.437C>T	p.Pro146Leu	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.171+27401C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437C>T (p.P146L) alteration is located in exon 5 (coding exon 3) of the PRRG1 gene. This alteration results from a C to T substitution at nucleotide position 437, causing the proline (P) at amino acid position 146 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;T;.;D;.
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M
PhyloP100		3.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.019	D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.44
MutPred		0.29		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.31
MPC		0.91
ClinPred		0.88	D
GERP RS		6.2
Varity_R		0.26
gMVP		0.72
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1271071931; hg19: chrX-37312654;