rs1462615503

Variant names:

• chrX-37453353-C-A
• rs1462615503
• NM_001142395.2:c.389C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-37453353-C-A
• chrX-37453353-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142395.2(PRRG1):​c.389C>A​(p.Thr130Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,204,799 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. T130I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: PRRG1 NM_001142395.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18535927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG1	NM_001142395.2	c.389C>A	p.Thr130Asn	missense_variant	Exon 4 of 4	ENST00000378628.9	NP_001135867.1
PRRG1	NM_000950.3	c.389C>A	p.Thr130Asn	missense_variant	Exon 5 of 5		NP_000941.1
PRRG1	NM_001173489.2	c.389C>A	p.Thr130Asn	missense_variant	Exon 5 of 5		NP_001166960.1
PRRG1	NM_001173490.2	c.389C>A	p.Thr130Asn	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.389C>A	p.Thr130Asn	missense_variant	Exon 4 of 4	1	NM_001142395.2	ENSP00000367894.4
ENSG00000250349	ENST00000465127.1	c.171+27353C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.00000918 AC: 1 AN: 108921 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000545 AC: 1 AN: 183363 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839997

Other (OTH) AF: 0.00 AC: 0 AN: 46018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000918 AC: 1 AN: 108921 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31243

African (AFR) AF: 0.0000335 AC: 1 AN: 29829

American (AMR) AF: 0.00 AC: 0 AN: 10083

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2609

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5745

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52396

Other (OTH) AF: 0.00 AC: 0 AN: 1446

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;T;T;T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	.;T;.;T;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	N;.;N;N;N
PhyloP100		1.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.18	N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.44	B;.;B;B;B
Vest4		0.34
MutPred		0.34		Loss of glycosylation at T130 (P = 5e-04);Loss of glycosylation at T130 (P = 5e-04);Loss of glycosylation at T130 (P = 5e-04);Loss of glycosylation at T130 (P = 5e-04);Loss of glycosylation at T130 (P = 5e-04);
MVP		0.53
MPC		0.31
ClinPred		0.096	T
GERP RS		3.8
Varity_R		0.16
gMVP		0.30
Mutation Taster		=89/11	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: rs1462615503; hg19: chrX-37312606;