rs3093266

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_019616.4(F7):c.740-10T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001635

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.144

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F7	NM_019616.4 linkuse as main transcript	c.740-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000346342.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
F7	ENST00000346342.8 linkuse as main transcript	c.740-10T>C	splice_polypyrimidine_tract_variant, intron_variant	1	NM_019616.4	P2	P08709-2
F7	ENST00000375581.3 linkuse as main transcript	c.806-10T>C	splice_polypyrimidine_tract_variant, intron_variant	1		A2	P08709-1
F7	ENST00000541084.5 linkuse as main transcript	c.554-10T>C	splice_polypyrimidine_tract_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

819

AN:

152212

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00495

AC:

1155

AN:

233218

Hom.:

AF XY:

0.00500

AC XY:

637

AN XY:

127302

show subpopulations

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 SAS exome

AF:

0.000485

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.:

Cov.:

AF XY:

0.00811

AC XY:

5758

AN XY:

710084

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.0000791

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.000497

Gnomad4 FIN exome

AF:

0.00766

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00553

GnomAD4 genome

AF:

0.00538

AC:

819

AN:

152330

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

372

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00763

Gnomad4 NFE

AF:

0.00904

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00477

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	F7: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Factor VII deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over