rs5970

Variant names:

• chr4-186284147-T-C
• rs5970
• NM_000128.4:c.1191T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000128.4(F11):​c.1191T>C​(p.Gly397Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,614,012 control chromosomes in the GnomAD database, including 18,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2152 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16275 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.76

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-186284147-T-C is Benign according to our data. Variant chr4-186284147-T-C is described in ClinVar as [Benign]. Clinvar id is 255176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284147-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.1191T>C	p.Gly397Gly	synonymous_variant	Exon 11 of 15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.1191T>C	p.Gly397Gly	synonymous_variant	Exon 11 of 15	1	NM_000128.4	ENSP00000384957.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24646 AN: 152018 Hom.: 2154 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0407

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.149 AC: 37471 AN: 251486 Hom.: 3147 AF XY: 0.154 AC XY: 20884 AN XY: 135914

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0458

Gnomad SAS exome AF: 0.221

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.145 AC: 212034 AN: 1461876 Hom.: 16275 Cov.: 33 AF XY: 0.148 AC XY: 107828 AN XY: 727238

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.0476

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.162 AC: 24652 AN: 152136 Hom.: 2152 Cov.: 33 AF XY: 0.163 AC XY: 12138 AN XY: 74382

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0406

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.151

Alfa AF: 0.152 Hom.: 2383

Bravo AF: 0.158

Asia WGS AF: 0.130 AC: 458 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Benign:2

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Plasma factor XI deficiency Benign:1

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.022
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5970; hg19: chr4-187205301; COSMIC: COSV53002167; COSMIC: COSV53002167;