NM_000313.4:c.346+1651C>T

Variant names:

• chr3-93908968-G-A
• rs4857037
• NM_000313.4:c.346+1651C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000313.4(PROS1):​c.346+1651C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,190 control chromosomes in the GnomAD database, including 60,601 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60601 hom., cov: 31)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• 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 recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• protein S deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• thrombophilia due to protein S deficiency, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

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.346+1651C>T		intron	N/A	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.442+1651C>T		intron	N/A	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.346+1651C>T		intron	N/A	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.346+1651C>T		intron	N/A	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.442+1651C>T		intron	N/A	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135648 AN: 152074 Hom.: 60561 Cov.: 31

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.882

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.892 AC: 135749 AN: 152190 Hom.: 60601 Cov.: 31 AF XY: 0.893 AC XY: 66479 AN XY: 74414

African (AFR) AF: 0.851 AC: 35332 AN: 41506

American (AMR) AF: 0.900 AC: 13746 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2987 AN: 3470

East Asian (EAS) AF: 0.890 AC: 4595 AN: 5162

South Asian (SAS) AF: 0.892 AC: 4307 AN: 4828

European-Finnish (FIN) AF: 0.938 AC: 9944 AN: 10602

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61993 AN: 68022

Other (OTH) AF: 0.881 AC: 1863 AN: 2114

Alfa AF: 0.894 Hom.: 9075

Bravo AF: 0.885

Asia WGS AF: 0.883 AC: 3073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.52
PhyloP100		-0.025
Mutation Taster		=100/0	polymorphism (auto)

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: rs4857037; hg19: chr3-93627812;