Genetic Variant RPTN:p.Gly560Asp (chr1-152155420-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001122965.1(RPTN):c.1679G>A(p.Gly560Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RPTN
NM_001122965.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0460

Variant links:

Genes affected

RPTN (HGNC:26809): (repetin) Predicted to enable calcium ion binding activity and transition metal ion binding activity. Predicted to be located in cytosol. Predicted to be active in cornified envelope. [provided by Alliance of Genome Resources, Apr 2022]

RPTN links:

PUDPP2 (HGNC:20195): (pseudouridine 5'-phosphatase pseudogene 2)

PUDPP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.073311985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPTN	NM_001122965.1 link	c.1679G>A	p.Gly560Asp	missense_variant	Exon 3 of 3	ENST00000316073.3	NP_001116437.1	Q6XPR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPTN	ENST00000316073.3 link	c.1679G>A	p.Gly560Asp	missense_variant	Exon 3 of 3	1	NM_001122965.1	ENSP00000317895.3		Q6XPR3
PUDPP2	ENST00000628080.1 link	n.48-30715G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151862

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74162

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1679G>A (p.G560D) alteration is located in exon 3 (coding exon 2) of the RPTN gene. This alteration results from a G to A substitution at nucleotide position 1679, causing the glycine (G) at amino acid position 560 to be replaced by an aspartic acid (D). 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

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.9

DANN

Benign

0.25

DEOGEN2

Benign

0.012

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.50

M_CAP

Benign

0.0017

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.051

Sift

Benign

0.071

Sift4G

Benign

0.14

Polyphen

0.019

Vest4

0.15

MutPred

0.43

Loss of MoRF binding (P = 0.0679);

MVP

0.35

MPC

0.025

ClinPred

0.077

GERP RS

3.1

Varity_R

0.092

gMVP

0.052

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over