NM_000313.4:c.*520A>C

Variant names:

• chr3-93873725-T-G
• rs9681204
• NM_000313.4:c.*520A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000313.4(PROS1):​c.*520A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 152,076 control chromosomes in the GnomAD database, including 46,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46213 hom., cov: 32)
  • Exomes 𝑓: 0.77 (618 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROS1 NM_000313.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 8 publications found

Genes affected

PROS1 (HGNC:9456): (protein S) This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

PROS1 Gene-Disease associations (from GenCC):

• thrombophilia due to protein S deficiency, autosomal dominant

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein S deficiency, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-93873725-T-G is Benign according to our data. Variant chr3-93873725-T-G is described in ClinVar as [Benign]. Clinvar id is 346871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.*520A>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.*520A>C		3_prime_UTR_variant	Exon 16 of 16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.*520A>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118197 AN: 151958 Hom.: 46173 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.748

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.769 AC: 1603 AN: 2084 Hom.: 618 Cov.: 0 AF XY: 0.760 AC XY: 807 AN XY: 1062

African (AFR) AF: 0.357 AC: 5 AN: 14

American (AMR) AF: 0.824 AC: 178 AN: 216

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 10 AN: 16

East Asian (EAS) AF: 0.672 AC: 39 AN: 58

South Asian (SAS) AF: 0.696 AC: 117 AN: 168

European-Finnish (FIN) AF: 0.682 AC: 15 AN: 22

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.785 AC: 1192 AN: 1518

Other (OTH) AF: 0.653 AC: 47 AN: 72

GnomAD4 genome AF: 0.778 AC: 118299 AN: 152076 Hom.: 46213 Cov.: 32 AF XY: 0.781 AC XY: 58035 AN XY: 74356

African (AFR) AF: 0.708 AC: 29379 AN: 41470

American (AMR) AF: 0.798 AC: 12191 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2150 AN: 3472

East Asian (EAS) AF: 0.784 AC: 4045 AN: 5160

South Asian (SAS) AF: 0.780 AC: 3765 AN: 4824

European-Finnish (FIN) AF: 0.877 AC: 9290 AN: 10588

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55106 AN: 67970

Other (OTH) AF: 0.748 AC: 1578 AN: 2110

Alfa AF: 0.755 Hom.: 2480

Bravo AF: 0.766

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.76
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs9681204; hg19: chr3-93592569;