rs78449232

chr3-93893056-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000313.4(PROS1):c.1032C>T(p.Ile344=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,888 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: PROS1 NM_000313.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-93893056-G-A is Benign according to our data. Variant chr3-93893056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 346884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00905 (1377/152232) while in subpopulation AFR AF= 0.0309 (1285/41530). AF 95% confidence interval is 0.0295. There are 21 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.1032C>T	p.Ile344=	synonymous_variant	10/15	ENST00000394236.9
PROS1	NM_001314077.2	c.1128C>T	p.Ile376=	synonymous_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.1032C>T	p.Ile344=	synonymous_variant	10/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1377 AN: 152114 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 251340 Hom.: 11 AF XY: 0.00175 AC XY: 238 AN XY: 135868

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00103 AC: 1508 AN: 1461656 Hom.: 17 Cov.: 31 AF XY: 0.000924 AC XY: 672 AN XY: 727142

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00905 AC: 1377 AN: 152232 Hom.: 21 Cov.: 32 AF XY: 0.00848 AC XY: 631 AN XY: 74438

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00374 Hom.: 6

Bravo AF: 0.0105

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.63
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs78449232; hg19: chr3-93611900;