3-93873865-T-A

Variant names:

• chr3-93873865-T-A
• rs138546241
• NM_000313.4:c.*380A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000313.4(PROS1):​c.*380A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 244,816 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: PROS1 NM_000313.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0220
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-93873865-T-A is Benign according to our data. Variant chr3-93873865-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 903198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00138 (210/152334) while in subpopulation AMR AF = 0.00386 (59/15300). AF 95% confidence interval is 0.00307. There are 2 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.*380A>T		3_prime_UTR	Exon 15 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.*380A>T		3_prime_UTR	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.*380A>T		3_prime_UTR	Exon 15 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.*380A>T		3_prime_UTR	Exon 15 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.*380A>T		3_prime_UTR	Exon 16 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152216 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00164 AC: 152 AN: 92482 Hom.: 1 Cov.: 0 AF XY: 0.00129 AC XY: 64 AN XY: 49456

African (AFR) AF: 0.000577 AC: 1 AN: 1732

American (AMR) AF: 0.00537 AC: 21 AN: 3910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2062

East Asian (EAS) AF: 0.00185 AC: 7 AN: 3790

South Asian (SAS) AF: 0.0000671 AC: 1 AN: 14906

European-Finnish (FIN) AF: 0.00916 AC: 41 AN: 4476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00115 AC: 65 AN: 56574

Other (OTH) AF: 0.00339 AC: 16 AN: 4716

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152334 Hom.: 2 Cov.: 33 AF XY: 0.00180 AC XY: 134 AN XY: 74502

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.00386 AC: 59 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.000691

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Thrombophilia due to protein S deficiency, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.4
DANN	Benign	0.67
PhyloP100		0.022
Mutation Taster		=100/0	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: rs138546241; hg19: chr3-93592709;