X-37425920-G-A

Variant names:

• chrX-37425920-G-A
• NM_001142395.2:c.91G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142395.2(PRRG1):​c.91G>A​(p.Gly31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.91G>A	p.Gly31Ser	missense_variant	Exon 3 of 4	ENST00000378628.9	NP_001135867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRG1	ENST00000378628.9	c.91G>A	p.Gly31Ser	missense_variant	Exon 3 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.91G>A	p.Gly31Ser	missense_variant	Exon 3 of 9	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91G>A (p.G31S) alteration is located in exon 4 (coding exon 2) of the PRRG1 gene. This alteration results from a G to A substitution at nucleotide position 91, causing the glycine (G) at amino acid position 31 to be replaced by a serine (S). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;D;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;D;D;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M;.;M;M;.;M;M;.
PhyloP100		8.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D;.;.
Vest4		0.73
MutPred		0.70		Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);Gain of phosphorylation at G31 (P = 0.0244);
MVP		0.71
MPC		0.90, 1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.84
Mutation Taster		=63/37	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

hg19: chrX-37285173;