chrX-37453364-C-A

Variant names:

• chrX-37453364-C-A
• rs145751381
• NM_001142395.2:c.400C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142395.2(PRRG1):​c.400C>A​(p.Pro134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,494 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. 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: not found (cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22502378).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.400C>A	p.Pro134Thr	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1
PRRG1	NM_000950.3	c.400C>A	p.Pro134Thr	missense_variant	Exon 5 of 5		NP_000941.1
PRRG1	NM_001173489.2	c.400C>A	p.Pro134Thr	missense_variant	Exon 5 of 5		NP_001166960.1
PRRG1	NM_001173490.2	c.400C>A	p.Pro134Thr	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.400C>A	p.Pro134Thr	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.171+27364C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097494 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362904

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.0000284 AC: 1 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 841455

Other (OTH) AF: 0.00 AC: 0 AN: 46075

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 17

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>A (p.P134T) 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 400, causing the proline (P) at amino acid position 134 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T;T;T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	.;T;.;T;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.0	L;.;L;L;L
PhyloP100		1.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.48	N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.22	T;D;T;T;T
Sift4G	Uncertain	0.052	T;D;T;T;T
Polyphen		0.025	B;.;B;B;B
Vest4		0.32
MutPred		0.35		Gain of phosphorylation at P134 (P = 0.0143);Gain of phosphorylation at P134 (P = 0.0143);Gain of phosphorylation at P134 (P = 0.0143);Gain of phosphorylation at P134 (P = 0.0143);Gain of phosphorylation at P134 (P = 0.0143);
MVP		0.46
MPC		0.42
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.47
Mutation Taster		=96/4	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: rs145751381; hg19: chrX-37312617;