Genetic Variant PROSER3:p.Pro259Leu (chr19-35766774-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_001367856.1(PROSER3):c.776C>T(p.Pro259Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000517 in 1,547,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

PROSER3
NM_001367856.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.274

Variant links:

Genes affected

PROSER3 (HGNC:25204): (proline and serine rich 3)

PROSER3 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=0.075494975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROSER3	NM_001367856.1 link	c.776C>T	p.Pro259Leu	missense_variant	Exon 8 of 11	ENST00000646935.2	NP_001354785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROSER3	ENST00000646935.2 link	c.776C>T	p.Pro259Leu	missense_variant	Exon 8 of 11		NM_001367856.1	ENSP00000496769.2		A0A2R8Y8D9

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000116

AC:

AN:

155192

Hom.:

AF XY:

0.0000975

AC XY:

AN XY:

82032

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.000715

Gnomad EAS exome

AF:

0.000459

Gnomad SAS exome

AF:

0.0000442

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000335

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000494

AC:

AN:

1395642

Hom.:

Cov.:

AF XY:

0.0000363

AC XY:

AN XY:

687946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000843

Gnomad4 ASJ exome

AF:

0.000598

Gnomad4 EAS exome

AF:

0.000168

Gnomad4 SAS exome

AF:

0.0000506

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000325

Gnomad4 OTH exome

AF:

0.0000865

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000453

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776C>T (p.P259L) alteration is located in exon 8 (coding exon 8) of the PROSER3 gene. This alteration results from a C to T substitution at nucleotide position 776, causing the proline (P) at amino acid position 259 to be replaced by a leucine (L). 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

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.0

DANN

Benign

0.21

DEOGEN2

Benign

0.096

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.41

M_CAP

Benign

0.011

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.071

Sift

Benign

0.18

Sift4G

Uncertain

0.029

Vest4

0.11

MutPred

0.19

Loss of glycosylation at P259 (P = 0.0186);

MVP

0.20

ClinPred

0.10

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.022

gMVP

0.063

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