rs6123

Variant names:

• chr3-93874275-T-C
• rs6123
• NM_000313.4:c.2001A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000313.4(PROS1):​c.2001A>G​(p.Pro667Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,070 control chromosomes in the GnomAD database, including 136,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P667P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (10408 hom., cov: 32)
  • Exomes 𝑓: 0.41 (126400 hom.)
• Consequence: PROS1 NM_000313.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.268
• Publications: 26 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• thrombophilia due to protein S deficiency, autosomal recessive

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-93874275-T-C is Benign according to our data. Variant chr3-93874275-T-C is described in ClinVar as Benign. ClinVar VariationId is 255811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000313.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	NM_000313.4	MANE Select	c.2001A>G	p.Pro667Pro	synonymous	Exon 15 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.2097A>G	p.Pro699Pro	synonymous	Exon 16 of 16	NP_001301006.1	A0A0S2Z4L3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	ENST00000394236.9	TSL:1 MANE Select	c.2001A>G	p.Pro667Pro	synonymous	Exon 15 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.1956A>G	p.Pro652Pro	synonymous	Exon 15 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.2097A>G	p.Pro699Pro	synonymous	Exon 16 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52984 AN: 151904 Hom.: 10400 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.427 AC: 107205 AN: 250796 AF XY: 0.433

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.560

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.411 AC: 600048 AN: 1461048 Hom.: 126400 Cov.: 51 AF XY: 0.415 AC XY: 301316 AN XY: 726848

African (AFR) AF: 0.139 AC: 4651 AN: 33448

American (AMR) AF: 0.488 AC: 21816 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8421 AN: 26110

East Asian (EAS) AF: 0.581 AC: 23012 AN: 39610

South Asian (SAS) AF: 0.506 AC: 43646 AN: 86234

European-Finnish (FIN) AF: 0.449 AC: 23960 AN: 53410

Middle Eastern (MID) AF: 0.381 AC: 2195 AN: 5758

European-Non Finnish (NFE) AF: 0.404 AC: 448487 AN: 1111436

Other (OTH) AF: 0.395 AC: 23860 AN: 60344

GnomAD4 genome AF: 0.349 AC: 53000 AN: 152022 Hom.: 10408 Cov.: 32 AF XY: 0.356 AC XY: 26444 AN XY: 74304

African (AFR) AF: 0.155 AC: 6447 AN: 41504

American (AMR) AF: 0.441 AC: 6737 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3466

East Asian (EAS) AF: 0.554 AC: 2871 AN: 5178

South Asian (SAS) AF: 0.501 AC: 2416 AN: 4824

European-Finnish (FIN) AF: 0.430 AC: 4537 AN: 10554

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27580 AN: 67910

Other (OTH) AF: 0.362 AC: 764 AN: 2112

Alfa AF: 0.393 Hom.: 34474

Bravo AF: 0.340

Asia WGS AF: 0.489 AC: 1696 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Thrombophilia due to protein S deficiency, autosomal dominant (2)
-	-	2	Thrombophilia due to protein S deficiency, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.7
DANN	Benign	0.66
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs6123; hg19: chr3-93593119; COSMIC: COSV67775574;