X-37453364-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142395.2(PRRG1):​c.400C>G​(p.Pro134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,206,834 control chromosomes in the GnomAD database, including 2 homozygotes. There are 566 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P134R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., 33 hem., cov: 22)
  • Exomes 𝑓: 0.0013 (2 hom. 533 hem.)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006713271).
• BS2: High Hemizygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.400C>G	p.Pro134Ala	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1
PRRG1	NM_000950.3	c.400C>G	p.Pro134Ala	missense_variant	Exon 5 of 5		NP_000941.1
PRRG1	NM_001173489.2	c.400C>G	p.Pro134Ala	missense_variant	Exon 5 of 5		NP_001166960.1
PRRG1	NM_001173490.2	c.400C>G	p.Pro134Ala	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>G	p.Pro134Ala	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.171+27364C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 105 AN: 109289 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00412

Gnomad FIN AF: 0.000172

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000690

GnomAD2 exomes AF: 0.00124 AC: 227 AN: 183377 AF XY: 0.00158

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00131 AC: 1437 AN: 1097494 Hom.: 2 Cov.: 31 AF XY: 0.00147 AC XY: 533 AN XY: 362904

African (AFR) AF: 0.000114 AC: 3 AN: 26388

American (AMR) AF: 0.000284 AC: 10 AN: 35203

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

East Asian (EAS) AF: 0.000265 AC: 8 AN: 30205

South Asian (SAS) AF: 0.00471 AC: 255 AN: 54125

European-Finnish (FIN) AF: 0.000345 AC: 14 AN: 40529

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4136

European-Non Finnish (NFE) AF: 0.00130 AC: 1096 AN: 841455

Other (OTH) AF: 0.00102 AC: 47 AN: 46075

GnomAD4 genome AF: 0.000960 AC: 105 AN: 109340 Hom.: 0 Cov.: 22 AF XY: 0.00104 AC XY: 33 AN XY: 31606

African (AFR) AF: 0.000133 AC: 4 AN: 30006

American (AMR) AF: 0.000788 AC: 8 AN: 10148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00413 AC: 10 AN: 2420

European-Finnish (FIN) AF: 0.000172 AC: 1 AN: 5802

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.00150 AC: 79 AN: 52492

Other (OTH) AF: 0.000682 AC: 1 AN: 1467

Alfa AF: 0.00110 Hom.: 17

Bravo AF: 0.000846

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00178 AC: 12

ExAC AF: 0.00160 AC: 194

EpiCase AF: 0.00153

EpiControl AF: 0.00113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.025	T;T;T;T;T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	.;T;.;T;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.0067	T;T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.81	L;.;L;L;L
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.15	N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.33	T;D;T;T;T
Sift4G	Uncertain	0.048	D;D;D;D;D
Polyphen		0.0	B;.;B;B;B
Vest4		0.093
MVP		0.48
MPC		0.26
ClinPred		0.0057	T
GERP RS		4.3
Varity_R		0.074
gMVP		0.40
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;