rs973760

Variant names:

• chr2-127422645-A-G
• rs973760
• NM_000312.4:c.238-272A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-127422645-A-G
• chr2-127422645-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000312.4(PROC):​c.238-272A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 152,096 control chromosomes in the GnomAD database, including 40,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.73 (40583 hom., cov: 32)
• Consequence: PROC NM_000312.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-127422645-A-G is Benign according to our data. Variant chr2-127422645-A-G is described in ClinVar as [Benign]. Clinvar id is 1245987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.238-272A>G		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.238-272A>G		intron_variant	Intron 3 of 8	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110824 AN: 151976 Hom.: 40574 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.733

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.729 AC: 110873 AN: 152096 Hom.: 40583 Cov.: 32 AF XY: 0.724 AC XY: 53821 AN XY: 74348

African (AFR) AF: 0.734 AC: 30482 AN: 41506

American (AMR) AF: 0.792 AC: 12114 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2828 AN: 3468

East Asian (EAS) AF: 0.573 AC: 2950 AN: 5144

South Asian (SAS) AF: 0.535 AC: 2579 AN: 4818

European-Finnish (FIN) AF: 0.711 AC: 7518 AN: 10580

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49915 AN: 67970

Other (OTH) AF: 0.724 AC: 1533 AN: 2116

Alfa AF: 0.743 Hom.: 5618

Bravo AF: 0.741

Asia WGS AF: 0.560 AC: 1948 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.38
DANN	Benign	0.64
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs973760; hg19: chr2-128180221;