Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000312.4(PROC):c.399C>T(p.Arg133Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,494,778 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 34)

Exomes 𝑓: 0.00041 ( 4 hom. )

Consequence

PROC
NM_000312.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0009557

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.461

Publications

2 publications found

Variant links:

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

PROC Gene-Disease associations (from GenCC):

hereditary thrombophilia due to congenital protein C deficiency
Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
thrombophilia due to protein C deficiency, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
thrombophilia due to protein C deficiency, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

PROC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 2-127423170-C-T is Benign according to our data. Variant chr2-127423170-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.461 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00389 (576/147938) while in subpopulation AFR AF = 0.0135 (552/40912). AF 95% confidence interval is 0.0126. There are 4 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000312.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PROC	NM_000312.4	MANE Select	c.399C>T	p.Arg133Arg	splice_region synonymous	Exon 5 of 9	NP_000303.1
PROC	NM_001375606.1		c.554C>T	p.Ala185Val	missense	Exon 4 of 8	NP_001362535.1
PROC	NM_001375607.1		c.483C>T	p.Arg161Arg	synonymous	Exon 5 of 8	NP_001362536.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PROC	ENST00000234071.8	TSL:1 MANE Select	c.399C>T	p.Arg133Arg	splice_region synonymous	Exon 5 of 9	ENSP00000234071.4
PROC	ENST00000409048.1	TSL:5	c.399C>T	p.Arg133Arg	synonymous	Exon 4 of 7	ENSP00000386679.1
PROC	ENST00000442644.5	TSL:3	c.399C>T	p.Arg133Arg	splice_region synonymous	Exon 5 of 7	ENSP00000411241.1

Frequencies

GnomAD3 genomes

AF:

0.00388

AC:

574

AN:

147822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00114

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:

0.0000300

Gnomad OTH

AF:

0.00195

GnomAD2 exomes

AF:

0.000882

AC:

163

AN:

184728

AF XY:

0.000702

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.000476

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.000406

AC:

547

AN:

1346840

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

206

AN XY:

666068

show subpopulations

African (AFR)

AF:

0.0156

AC:

466

AN:

29928

American (AMR)

AF:

0.000645

AC:

AN:

38764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22236

East Asian (EAS)

AF:

0.00

AC:

AN:

30952

South Asian (SAS)

AF:

0.0000492

AC:

AN:

81332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41162

Middle Eastern (MID)

AF:

0.000409

AC:

AN:

4890

European-Non Finnish (NFE)

AF:

0.00000670

AC:

AN:

1044124

Other (OTH)

AF:

0.000804

AC:

AN:

53452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00389

AC:

576

AN:

147938

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

270

AN XY:

72250

show subpopulations

African (AFR)

AF:

0.0135

AC:

552

AN:

40912

American (AMR)

AF:

0.00113

AC:

AN:

14998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

4720

South Asian (SAS)

AF:

0.00

AC:

AN:

4484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9608

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66594

Other (OTH)

AF:

0.00193

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00457

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thrombophilia due to protein C deficiency, autosomal dominant (3)

PROC-related disorder (1)

Reduced protein C activity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

-0.46

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00096

dbscSNV1_RF

Benign

0.088

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs200045749

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over