X-37425869-A-G

Variant names:

• chrX-37425869-A-G
• NM_001142395.2:c.40A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001142395.2(PRRG1):​c.40A>G​(p.Ile14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05318898).
• BP6: Variant X-37425869-A-G is Benign according to our data. Variant chrX-37425869-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3219720.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.40A>G	p.Ile14Val	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.40A>G	p.Ile14Val	missense_variant	Exon 3 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.40A>G	p.Ile14Val	missense_variant	Exon 3 of 9	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 07, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.0
DANN	Benign	0.58
DEOGEN2	Benign	0.012	T;T;T;T;T;T;.;.
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.45	.;T;.;T;T;.;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	-1.6	N;.;N;N;.;N;N;.
PhyloP100		1.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.26	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;T;T;T;T;T;T;D
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;B;.;.
Vest4		0.14
MutPred		0.37		Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);Gain of MoRF binding (P = 0.119);
MVP		0.23
MPC		0.22, 0.49
ClinPred		0.026	T
GERP RS		2.2
Varity_R		0.032
gMVP		0.37
Mutation Taster		=95/5	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-37285122;