3-93873791-C-T

Variant names:

• chr3-93873791-C-T
• rs539871594
• NM_000313.4:c.*454G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000313.4(PROS1):​c.*454G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 179,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PROS1 NM_000313.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0500
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-93873791-C-T is Benign according to our data. Variant chr3-93873791-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 903196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00239 (363/152038) while in subpopulation AFR AF = 0.00827 (343/41466). AF 95% confidence interval is 0.00755. There are 1 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.*454G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.*454G>A		3_prime_UTR_variant	Exon 16 of 16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.*454G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 151920 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00834

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000180 AC: 5 AN: 27832 Hom.: 0 Cov.: 0 AF XY: 0.000137 AC XY: 2 AN XY: 14652

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00521 AC: 1 AN: 192

American (AMR) AF: 0.000495 AC: 1 AN: 2020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 442

East Asian (EAS) AF: 0.00 AC: 0 AN: 1206

South Asian (SAS) AF: 0.00 AC: 0 AN: 3494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.000167 AC: 3 AN: 18006

Other (OTH) AF: 0.00 AC: 0 AN: 1442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.018235), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00239 AC: 363 AN: 152038 Hom.: 1 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74326

African (AFR) AF: 0.00827 AC: 343 AN: 41466

American (AMR) AF: 0.000720 AC: 11 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.00282

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.59
PhyloP100		0.050
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs539871594; hg19: chr3-93592635;