X-37453365-C-T

Variant names:

• chrX-37453365-C-T
• rs782391292
• NM_001142395.2:c.401C>T

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.401C>T​(p.Pro134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000854 in 1,206,725 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts 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 0.000018 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000092 (0 hom. 27 hem.)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 2 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=0.20064116).
• BS2: High Hemizygotes in GnomAdExome4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.401C>T	p.Pro134Leu	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1
PRRG1	NM_000950.3	c.401C>T	p.Pro134Leu	missense_variant	Exon 5 of 5		NP_000941.1
PRRG1	NM_001173489.2	c.401C>T	p.Pro134Leu	missense_variant	Exon 5 of 5		NP_001166960.1
PRRG1	NM_001173490.2	c.401C>T	p.Pro134Leu	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.401C>T	p.Pro134Leu	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.171+27365C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0000183 AC: 2 AN: 109248 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000572

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183353 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000920 AC: 101 AN: 1097477 Hom.: 0 Cov.: 31 AF XY: 0.0000744 AC XY: 27 AN XY: 362909

African (AFR) AF: 0.00 AC: 0 AN: 26391

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00328 AC: 99 AN: 30204

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841434

Other (OTH) AF: 0.0000217 AC: 1 AN: 46077

GnomAD4 genome AF: 0.0000183 AC: 2 AN: 109248 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31524

African (AFR) AF: 0.00 AC: 0 AN: 29914

American (AMR) AF: 0.00 AC: 0 AN: 10132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2613

East Asian (EAS) AF: 0.000572 AC: 2 AN: 3499

South Asian (SAS) AF: 0.00 AC: 0 AN: 2430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52504

Other (OTH) AF: 0.00 AC: 0 AN: 1450

Alfa AF: 0.0000262 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;T;T;T;T
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	.;T;.;T;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.4	L;.;L;L;L
PhyloP100		2.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.17	N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.19	T;D;T;T;T
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.025	B;.;B;B;B
Vest4		0.32
MutPred		0.37		Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);Loss of glycosylation at P134 (P = 0.0057);
MVP		0.43
MPC		0.39
ClinPred		0.075	T
GERP RS		5.3
Varity_R		0.089
gMVP		0.53
Mutation Taster		=97/3	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: rs782391292; hg19: chrX-37312618;