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GeneBe

20-35174795-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006404.5(PROCR):c.164C>T(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PROCR
NM_006404.5 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71
Variant links:
Genes affected
PROCR (HGNC:9452): (protein C receptor) The protein encoded by this gene is a receptor for activated protein C, a serine protease activated by and involved in the blood coagulation pathway. The encoded protein is an N-glycosylated type I membrane protein that enhances the activation of protein C. Mutations in this gene have been associated with venous thromboembolism and myocardial infarction, as well as with late fetal loss during pregnancy. The encoded protein may also play a role in malarial infection and has been associated with cancer. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PROCRNM_006404.5 linkuse as main transcriptc.164C>T p.Thr55Met missense_variant 2/4 ENST00000216968.5
MMP24-AS1-EDEM2NM_001355008.2 linkuse as main transcriptc.-101-8924G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PROCRENST00000216968.5 linkuse as main transcriptc.164C>T p.Thr55Met missense_variant 2/41 NM_006404.5 P1
ENST00000615962.1 linkuse as main transcriptn.125G>A non_coding_transcript_exon_variant 1/1
PROCRENST00000635377.1 linkuse as main transcriptc.65C>T p.Thr22Met missense_variant 1/45

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000263
AC:
4
AN:
152106
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251370
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000458
AC:
67
AN:
1461892
Hom.:
0
Cov.:
46
AF XY:
0.0000385
AC XY:
28
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
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:
0.0000576
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000263
AC:
4
AN:
152106
Hom.:
0
Cov.:
29
AF XY:
0.0000135
AC XY:
1
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000642
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 26, 2022The c.164C>T (p.T55M) alteration is located in exon 2 (coding exon 2) of the PROCR gene. This alteration results from a C to T substitution at nucleotide position 164, causing the threonine (T) at amino acid position 55 to be replaced by a methionine (M). 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
Uncertain
0.55
BayesDel_addAF
Benign
-0.0014
T
BayesDel_noAF
Uncertain
-0.060
Cadd
Pathogenic
26
Dann
Uncertain
1.0
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.84
T
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-4.1
D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.68
MutPred
0.79
Loss of disorder (P = 0.1092);
MVP
0.85
MPC
1.2
ClinPred
0.71
D
GERP RS
5.2
Varity_R
0.46
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs746777605; hg19: chr20-33762598; COSMIC: COSV99405830; COSMIC: COSV99405830; API