rs73846070

Variant names:

• chr3-93927257-G-A
• rs73846070
• NM_000313.4:c.227C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_001314077.2(PROS1):​c.323C>T​(p.Pro108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,612,234 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P108P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: PROS1 NM_001314077.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.96
• 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 -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.58456 (below the threshold of 3.09). Trascript score misZ: 1.9528 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein S deficiency, autosomal dominant, thrombophilia due to protein S deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein S deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01530534).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00231 (352/152208) while in subpopulation AMR AF = 0.00641 (98/15292). AF 95% confidence interval is 0.00538. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001314077.2. 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.227C>T	p.Pro76Leu	missense	Exon 2 of 15	NP_000304.2
	PROS1	NM_001314077.2		c.323C>T	p.Pro108Leu	missense	Exon 3 of 16	NP_001301006.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	ENST00000394236.9	TSL:1 MANE Select	c.227C>T	p.Pro76Leu	missense	Exon 2 of 15	ENSP00000377783.3
	PROS1	ENST00000407433.6	TSL:1	c.227C>T	p.Pro76Leu	missense	Exon 2 of 15	ENSP00000385794.2
	PROS1	ENST00000472684.2	TSL:5	c.-167C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000419616.2

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152090 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00171 AC: 431 AN: 251376 AF XY: 0.00146

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00126 AC: 1841 AN: 1460026 Hom.: 5 Cov.: 31 AF XY: 0.00125 AC XY: 911 AN XY: 726306

African (AFR) AF: 0.00527 AC: 176 AN: 33410

American (AMR) AF: 0.00403 AC: 180 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 101 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000627 AC: 54 AN: 86176

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53404

Middle Eastern (MID) AF: 0.00793 AC: 34 AN: 4288

European-Non Finnish (NFE) AF: 0.00101 AC: 1121 AN: 1111978

Other (OTH) AF: 0.00221 AC: 133 AN: 60232

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152208 Hom.: 2 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74412

African (AFR) AF: 0.00393 AC: 163 AN: 41522

American (AMR) AF: 0.00641 AC: 98 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00181 Hom.: 3

Bravo AF: 0.00272

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Thrombophilia due to protein S deficiency, autosomal dominant (3)
-	1	-	not provided (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.67
Sift	Benign	0.080	T
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.99
MPC		0.51
ClinPred		0.030	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.40
gMVP		0.65
Mutation Taster		=288/12	polymorphism

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: rs73846070; hg19: chr3-93646101;