3-93879306-A-G

Variant names:

• chr3-93879306-A-G
• rs121918472
• NM_000313.4:c.1501T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BS1_Supporting BS2

The NM_000313.4(PROS1):​c.1501T>C​(p.Ser501Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,946 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S501A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:10 B:1
• Conservation: PhyloP100: -0.0830
• Publications: 30 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: Likely_benign. The variant received -6 ACMG points.

• PM1: In a domain Laminin G-like 2 (size 182) in uniprot entity PROS_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000313.4
• 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=0.009359419).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00242 (369/152304) while in subpopulation NFE AF = 0.00397 (270/68030). AF 95% confidence interval is 0.00358. There are 0 homozygotes in GnomAd4. There are 171 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 GnomAdExome4 at 8 AD,AR,SD gene

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.1501T>C	p.Ser501Pro	missense	Exon 13 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.1597T>C	p.Ser533Pro	missense	Exon 14 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.1501T>C	p.Ser501Pro	missense	Exon 13 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.1456T>C	p.Ser486Pro	missense	Exon 13 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.1597T>C	p.Ser533Pro	missense	Exon 14 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00202 AC: 509 AN: 251434 AF XY: 0.00218

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00317 AC: 4631 AN: 1461642 Hom.: 8 Cov.: 31 AF XY: 0.00313 AC XY: 2274 AN XY: 727128

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86250

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00378 AC: 4207 AN: 1111800

Other (OTH) AF: 0.00277 AC: 167 AN: 60388

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74484

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 68030

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

Alfa AF: 0.00285 Hom.: 0

Bravo AF: 0.00254

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	-	Thrombophilia due to protein S deficiency, autosomal dominant (4)
1	2	-	not provided (3)
-	1	1	not specified (2)
-	1	-	Hereditary thrombophilia due to congenital protein S deficiency (1)
-	1	-	Optic atrophy (1)
1	-	-	Protein S Heerlen (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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	6.5
DANN	Benign	0.83
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.083
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.13	T
Sift4G	Benign	0.099	T
Polyphen		0.84	P
Vest4		0.35
MVP		0.79
MPC		0.29
ClinPred		0.0041	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58
Mutation Taster		=99/1	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: rs121918472; hg19: chr3-93598150;