rs3733403

Variant names:

• chr4-186265981-C-G
• rs3733403
• NM_000128.4:c.-316C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-186265981-C-G
• chr4-186265981-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000128.4(F11):​c.-316C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,142 control chromosomes in the GnomAD database, including 3,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3185 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: F11 NM_000128.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.264

Genes affected

F11 (HGNC:3529): (coagulation factor XI) This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-186265981-C-G is Benign according to our data. Variant chr4-186265981-C-G is described in ClinVar as [Benign]. Clinvar id is 348368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186265981-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.-316C>G		upstream_gene_variant		ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.-316C>G		upstream_gene_variant		1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.-316C>G		upstream_gene_variant		2		ENSP00000424479.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27394 AN: 152022 Hom.: 3185 Cov.: 33

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.153

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.180 AC: 27417 AN: 152142 Hom.: 3185 Cov.: 33 AF XY: 0.182 AC XY: 13514 AN XY: 74376

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.151

Alfa AF: 0.107 Hom.: 693

Bravo AF: 0.184

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3733403; hg19: chr4-187187135;