rs8178626

Variant names:

• chr3-93909610-A-T
• rs8178626
• NM_000313.4:c.346+1009T>A

Variant summary

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

The NM_000313.4(PROS1):​c.346+1009T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,820 control chromosomes in the GnomAD database, including 18,124 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 0.47 (18124 hom., cov: 31)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.286
• Publications: 3 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 (SAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.346+1009T>A		intron_variant	Intron 4 of 14	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.442+1009T>A		intron_variant	Intron 5 of 15		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.346+1009T>A		intron_variant	Intron 4 of 14	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71181 AN: 151700 Hom.: 18118 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.469 AC: 71206 AN: 151820 Hom.: 18124 Cov.: 31 AF XY: 0.476 AC XY: 35282 AN XY: 74196

African (AFR) AF: 0.245 AC: 10154 AN: 41384

American (AMR) AF: 0.528 AC: 8031 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1671 AN: 3466

East Asian (EAS) AF: 0.624 AC: 3217 AN: 5158

South Asian (SAS) AF: 0.628 AC: 3019 AN: 4806

European-Finnish (FIN) AF: 0.570 AC: 6003 AN: 10534

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37447 AN: 67948

Other (OTH) AF: 0.486 AC: 1021 AN: 2102

Alfa AF: 0.505 Hom.: 2543

Bravo AF: 0.452

Asia WGS AF: 0.585 AC: 2032 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	1.3
DANN	Benign	0.50
PhyloP100		0.29
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: rs8178626; hg19: chr3-93628454;