NM_000313.4:c.77-145G>A

Variant names:

• chr3-93927552-C-T
• rs8178610
• NM_000313.4:c.77-145G>A

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.77-145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 964,236 control chromosomes in the GnomAD database, including 86,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10729 hom., cov: 30)
  • Exomes 𝑓: 0.42 (75688 hom.)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.146
• Publications: 16 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=-0.78).
• BP6: Variant 3-93927552-C-T is Benign according to our data. Variant chr3-93927552-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.77-145G>A		intron_variant	Intron 1 of 14	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.173-145G>A		intron_variant	Intron 2 of 15		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.77-145G>A		intron_variant	Intron 1 of 14	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53824 AN: 151642 Hom.: 10723 Cov.: 30

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.422 AC: 342726 AN: 812476 Hom.: 75688 AF XY: 0.427 AC XY: 175917 AN XY: 412398

African (AFR) AF: 0.142 AC: 2741 AN: 19254

American (AMR) AF: 0.319 AC: 6797 AN: 21300

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 5239 AN: 16742

East Asian (EAS) AF: 0.535 AC: 17517 AN: 32732

South Asian (SAS) AF: 0.505 AC: 26482 AN: 52438

European-Finnish (FIN) AF: 0.480 AC: 15119 AN: 31530

Middle Eastern (MID) AF: 0.412 AC: 1114 AN: 2702

European-Non Finnish (NFE) AF: 0.422 AC: 252359 AN: 597510

Other (OTH) AF: 0.401 AC: 15358 AN: 38268

GnomAD4 genome AF: 0.355 AC: 53834 AN: 151760 Hom.: 10729 Cov.: 30 AF XY: 0.360 AC XY: 26679 AN XY: 74132

African (AFR) AF: 0.159 AC: 6599 AN: 41406

American (AMR) AF: 0.347 AC: 5285 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3472

East Asian (EAS) AF: 0.524 AC: 2696 AN: 5146

South Asian (SAS) AF: 0.502 AC: 2418 AN: 4812

European-Finnish (FIN) AF: 0.468 AC: 4891 AN: 10458

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29514 AN: 67916

Other (OTH) AF: 0.367 AC: 773 AN: 2106

Alfa AF: 0.420 Hom.: 7188

Bravo AF: 0.334

Asia WGS AF: 0.481 AC: 1669 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 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	-0.78
CADD	Benign	2.7
DANN	Benign	0.83
PhyloP100		0.15
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: rs8178610; hg19: chr3-93646396;