3-93926203-T-C

Variant names:

• chr3-93926203-T-C
• rs4857343
• NM_000313.4:c.234+1047A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000313.4(PROS1):​c.234+1047A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 152,110 control chromosomes in the GnomAD database, including 47,359 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.79 (47359 hom., cov: 32)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.753
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.234+1047A>G		intron_variant	Intron 2 of 14	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.330+1047A>G		intron_variant	Intron 3 of 15		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.234+1047A>G		intron_variant	Intron 2 of 14	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119741 AN: 151992 Hom.: 47317 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.881

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.754

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

GnomAD4 genome AF: 0.788 AC: 119843 AN: 152110 Hom.: 47359 Cov.: 32 AF XY: 0.790 AC XY: 58786 AN XY: 74376

African (AFR) AF: 0.734 AC: 30453 AN: 41474

American (AMR) AF: 0.796 AC: 12167 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2129 AN: 3464

East Asian (EAS) AF: 0.784 AC: 4048 AN: 5164

South Asian (SAS) AF: 0.784 AC: 3774 AN: 4814

European-Finnish (FIN) AF: 0.881 AC: 9335 AN: 10592

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55549 AN: 68004

Other (OTH) AF: 0.754 AC: 1592 AN: 2112

Alfa AF: 0.799 Hom.: 62691

Bravo AF: 0.777

Asia WGS AF: 0.773 AC: 2688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.32
DANN	Benign	0.59
PhyloP100		-0.75
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: rs4857343; hg19: chr3-93645047;