rs3093266

Variant names:

• chr13-113118403-T-C
• rs3093266
• NM_019616.4:c.740-10T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-113118403-T-C
• chr13-113118403-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_019616.4(F7):​c.740-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 1,586,184 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0054 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (77 hom.)
• Consequence: F7 NM_019616.4 intron
• Scores: Splicing: ADA: 0.0001635
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.144
• Publications: 5 publications found

Genes affected

F7 (HGNC:3544): (coagulation factor VII) This gene encodes coagulation factor VII which is a vitamin K-dependent factor essential for hemostasis. This factor circulates in the blood in a zymogen form, and is converted to an active form by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Upon activation of the factor VII, a heavy chain containing a catalytic domain and a light chain containing 2 EGF-like domains are generated, and two chains are held together by a disulfide bond. In the presence of factor III and calcium ions, the activated factor then further activates the coagulation cascade by converting factor IX to factor IXa and/or factor X to factor Xa. Defects in this gene can cause coagulopathy. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing to generate mature polypeptides. [provided by RefSeq, Aug 2015]

F7 Gene-Disease associations (from GenCC):

• congenital factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics
• factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-113118403-T-C is Benign according to our data. Variant chr13-113118403-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255220.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00538 (819/152330) while in subpopulation NFE AF = 0.00904 (615/68024). AF 95% confidence interval is 0.00845. There are 3 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4	c.740-10T>C		intron_variant	Intron 7 of 7	ENST00000346342.8	NP_062562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F7	ENST00000346342.8	c.740-10T>C		intron_variant	Intron 7 of 7	1	NM_019616.4	ENSP00000329546.4
F7	ENST00000375581.3	c.806-10T>C		intron_variant	Intron 8 of 8	1		ENSP00000364731.3
F7	ENST00000541084.5	c.554-10T>C		intron_variant	Intron 5 of 5	2		ENSP00000442051.2

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 819 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00495 AC: 1155 AN: 233218 AF XY: 0.00500

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00802

Gnomad NFE exome AF: 0.00866

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00836 AC: 11989 AN: 1433854 Hom.: 77 Cov.: 33 AF XY: 0.00811 AC XY: 5758 AN XY: 710084

African (AFR) AF: 0.00123 AC: 41 AN: 33202

American (AMR) AF: 0.00159 AC: 70 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.0000791 AC: 2 AN: 25270

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39274

South Asian (SAS) AF: 0.000497 AC: 42 AN: 84444

European-Finnish (FIN) AF: 0.00766 AC: 335 AN: 43710

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.0102 AC: 11168 AN: 1098798

Other (OTH) AF: 0.00553 AC: 328 AN: 59336

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00499 AC XY: 372 AN XY: 74492

African (AFR) AF: 0.00185 AC: 77 AN: 41580

American (AMR) AF: 0.00268 AC: 41 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00904 AC: 615 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00431 Hom.: 0

Bravo AF: 0.00477

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F7: BS2 -

Factor VII deficiency Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.28
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0060
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: rs3093266; hg19: chr13-113772717;