rs6122

Variant names:

• chr3-93927251-G-A
• rs6122
• NM_000313.4:c.233C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-93927251-G-A
• chr3-93927251-G-C
• chr3-93927251-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PP2 PP3_Moderate PP5

The NM_000313.4(PROS1):​c.233C>T​(p.Thr78Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000253694: Experimental studies have shown that this missense change affects PROS1 function (PMID:12351389)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T78T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: PROS1 NM_000313.4 missense, splice_region
• Scores: Splicing: ADA: 0.9871
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 9.06
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000253694: Experimental studies have shown that this missense change affects PROS1 function (PMID: 12351389).; SCV005870251: Published functional studies demonstrate a damaging effect on protein binding and function (PMID: 12351389); SCV005400057: "This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 and COS-1 cells demonstrated reduced enzyme activity and protein expression, whereas patient cells showed reduced protein S activity and only slightly reduced free protein S (PMID: 34729451, PMID: 12351389)."; SCV005415723: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a domain Gla (size 45) in uniprot entity PROS_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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, hereditary thrombophilia due to congenital protein S deficiency, thrombophilia due to protein S deficiency, autosomal recessive, protein S deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 3-93927251-G-A is Pathogenic according to our data. Variant chr3-93927251-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215991.

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.233C>T	p.Thr78Met	missense splice_region	Exon 2 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.329C>T	p.Thr110Met	missense splice_region	Exon 3 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.233C>T	p.Thr78Met	missense splice_region	Exon 2 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.233C>T	p.Thr78Met	missense splice_region	Exon 2 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000472684.2	TSL:5	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000419616.2	C9K0R0

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251352 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1459970 Hom.: 0 Cov.: 31 AF XY: 0.0000620 AC XY: 45 AN XY: 726284

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4248

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111966

Other (OTH) AF: 0.0000498 AC: 3 AN: 60230

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
-	1	-	Deep venous thrombosis (1)
1	-	-	PROS1-related disorder (1)
1	-	-	Protein S deficiency disease (1)
1	-	-	Thrombophilia due to protein S deficiency, autosomal dominant (1)
1	-	-	Thrombophilia due to protein S deficiency, autosomal dominant;C3281092:Thrombophilia due to protein S deficiency, autosomal recessive (1)
1	-	-	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MVP		1.0
MPC		0.86
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.81
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.64
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: rs6122; hg19: chr3-93646095;