3-93879279-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000313.4(PROS1):​c.1528G>A​(p.Val510Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,614,028 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

PROS1
NM_000313.4 missense

Scores

7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:6O:1

Conservation

PhyloP100: -0.0910
Variant links:
Genes affected
PROS1 (HGNC:9456): (protein S) This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a domain Laminin G-like 2 (size 182) in uniprot entity PROS_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000313.4
BP4
Computational evidence support a benign effect (MetaRNN=0.009276807).
BP6
Variant 3-93879279-C-T is Benign according to our data. Variant chr3-93879279-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161343.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=3}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00351 (534/152260) while in subpopulation AFR AF= 0.0118 (491/41542). AF 95% confidence interval is 0.011. There are 5 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PROS1NM_000313.4 linkc.1528G>A p.Val510Met missense_variant Exon 13 of 15 ENST00000394236.9 NP_000304.2 P07225A0A0S2Z4K3
PROS1NM_001314077.2 linkc.1624G>A p.Val542Met missense_variant Exon 14 of 16 NP_001301006.1 P07225A0A0S2Z4L3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PROS1ENST00000394236.9 linkc.1528G>A p.Val510Met missense_variant Exon 13 of 15 1 NM_000313.4 ENSP00000377783.3 P07225

Frequencies

GnomAD3 genomes
AF:
0.00350
AC:
533
AN:
152142
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000879
AC:
221
AN:
251446
Hom.:
3
AF XY:
0.000633
AC XY:
86
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.0112
Gnomad AMR exome
AF:
0.000549
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000341
AC:
499
AN:
1461768
Hom.:
1
Cov.:
31
AF XY:
0.000296
AC XY:
215
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.0109
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.000536
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.000927
GnomAD4 genome
AF:
0.00351
AC:
534
AN:
152260
Hom.:
5
Cov.:
32
AF XY:
0.00337
AC XY:
251
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0118
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000205
Hom.:
0
Bravo
AF:
0.00400
ESP6500AA
AF:
0.0109
AC:
48
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.00106
AC:
129
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Uncertain:1Benign:2Other:1
-
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

May 01, 2015
Russ Altman Lab, Stanford University
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: case-control;research

- -

not provided Uncertain:2Benign:1
Dec 13, 2022
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS4, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jan 10, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BS2, PM1_supporting, PS3, PS4_moderate -

Protein S deficiency disease Pathogenic:1
-
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

PROS1-related disorder Benign:1
Jan 29, 2021
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thrombophilia due to protein S deficiency, autosomal dominant;C3281092:Thrombophilia due to protein S deficiency, autosomal recessive Benign:1
Jul 30, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Thrombophilia due to protein S deficiency, autosomal recessive Benign:1
Jan 08, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D;.;.;D;.;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.14
N
LIST_S2
Uncertain
0.86
.;D;D;D;D;D
MetaRNN
Benign
0.0093
T;T;T;T;T;T
MetaSVM
Benign
-0.41
T
MutationAssessor
Uncertain
2.5
M;.;.;M;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.7
N;.;.;.;.;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.028
D;.;.;.;.;.
Sift4G
Uncertain
0.035
D;.;.;.;.;.
Polyphen
0.58
P;.;.;P;.;.
Vest4
0.42
MVP
0.71
MPC
0.25
ClinPred
0.0055
T
GERP RS
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.10
gMVP
0.75

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.

Other links and lift over

dbSNP: rs138925964; hg19: chr3-93598123; API