rs1553423955

Variant names:

• chr2-127422916-G-A
• rs1553423955
• NM_000312.4:c.238-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000312.4(PROC):​c.238-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000141 in 1,417,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PROC NM_000312.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.38
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.7, offset of -29, new splice context is: cctccgcacaccggctgcAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-127422916-G-A is Pathogenic according to our data. Variant chr2-127422916-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 536971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.238-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 8	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.238-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 8	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417006 Hom.: 0 Cov.: 36 AF XY: 0.00000143 AC XY: 1 AN XY: 701304

African (AFR) AF: 0.00 AC: 0 AN: 32078

American (AMR) AF: 0.00 AC: 0 AN: 38098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 36564

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090224

Other (OTH) AF: 0.00 AC: 0 AN: 58716

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:1

Sep 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 3 of the PROC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PROC are known to be pathogenic (PMID: 17152060). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 536971). Disruption of this splice site has been observed in individual(s) with clinical features of PROC-related conditions (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		6.4
GERP RS		4.0
PromoterAI		0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -28
DS_AL_spliceai		0.98		Position offset: 1

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

Other links and lift over

dbSNP: rs1553423955; hg19: chr2-128180492;