Genetic Variant PROC:c.-33C>T (chr2-127418481-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000312.4(PROC):c.-33C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,289,792 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 16 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 10 hom. )

Consequence

PROC
NM_000312.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.09

Publications

1 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):

thrombophilia due to protein C deficiency, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
hereditary thrombophilia due to congenital protein C deficiency
Inheritance: SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.078).

BP6

Variant 2-127418481-C-T is Benign according to our data. Variant chr2-127418481-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 331100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1220/152292) while in subpopulation AFR AF = 0.0274 (1137/41550). AF 95% confidence interval is 0.026. There are 16 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 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	Effect	Exon Rank	Protein	UniProt
PROC	NM_000312.4	MANE Select	c.-33C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_000303.1	P04070-1
PROC	NM_000312.4	MANE Select	c.-33C>T	5_prime_UTR	Exon 1 of 9	NP_000303.1	P04070-1
PROC	NM_001375605.1		c.-33C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001362534.1	E7END6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PROC	ENST00000234071.8	TSL:1 MANE Select	c.-33C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000234071.4	P04070-1
PROC	ENST00000234071.8	TSL:1 MANE Select	c.-33C>T	5_prime_UTR	Exon 1 of 9	ENSP00000234071.4	P04070-1
PROC	ENST00000883860.1		c.-33C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000553919.1

Frequencies

GnomAD3 genomes

AF:

0.00795

AC:

1210

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

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:

0.000206

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00171

AC:

234

AN:

137018

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000869

AC:

989

AN:

1137500

Hom.:

Cov.:

AF XY:

0.000783

AC XY:

437

AN XY:

558050

show subpopulations

African (AFR)

AF:

0.0302

AC:

737

AN:

24414

American (AMR)

AF:

0.00205

AC:

AN:

28266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15942

East Asian (EAS)

AF:

0.00

AC:

AN:

12840

South Asian (SAS)

AF:

0.000144

AC:

AN:

76204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13064

Middle Eastern (MID)

AF:

0.00273

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.000111

AC:

102

AN:

920834

Other (OTH)

AF:

0.00166

AC:

AN:

41534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00801

AC:

1220

AN:

152292

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

588

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0274

AC:

1137

AN:

41550

American (AMR)

AF:

0.00379

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68018

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.00900

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

PROC-related disorder (1)

Thrombophilia due to protein C deficiency, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.7

(source)

DANN

Benign

0.74

PhyloP100

-2.1

PromoterAI

-0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=93/7

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over