rs519650

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000131.5(F7):c.805+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,574,426 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 22 hom. )

Consequence

F7
NM_000131.5 splice_region, intron

Scores

Splicing: ADA: 0.001902

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.871

Publications

1 publications found

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 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

F7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 13-113117603-A-G is Benign according to our data. Variant chr13-113117603-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402841.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000131.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
F7	NM_019616.4	MANE Select	c.739+7A>G	splice_region intron	N/A	NP_062562.1
F7	NM_000131.5		c.805+7A>G	splice_region intron	N/A	NP_000122.1
F7	NM_001267554.2		c.553+7A>G	splice_region intron	N/A	NP_001254483.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
F7	ENST00000346342.8	TSL:1 MANE Select	c.739+7A>G	splice_region intron	N/A	ENSP00000329546.4
F7	ENST00000375581.3	TSL:1	c.805+7A>G	splice_region intron	N/A	ENSP00000364731.3
F7	ENST00000891255.1		c.952+7A>G	splice_region intron	N/A	ENSP00000561314.1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

359

AN:

145020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000760

Gnomad AMI

AF:

0.00814

Gnomad AMR

AF:

0.00239

Gnomad ASJ

AF:

0.00699

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000219

Gnomad FIN

AF:

0.00441

Gnomad MID

AF:

0.00340

Gnomad NFE

AF:

0.00333

Gnomad OTH

AF:

0.000982

GnomAD2 exomes

AF:

0.00395

AC:

984

AN:

248898

AF XY:

0.00377

show subpopulations

Gnomad AFR exome

AF:

0.000804

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.00954

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00285

Gnomad NFE exome

AF:

0.00551

Gnomad OTH exome

AF:

0.00526

GnomAD4 exome

AF:

0.00410

AC:

5858

AN:

1429294

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

2986

AN XY:

711278

show subpopulations

African (AFR)

AF:

0.000692

AC:

AN:

33220

American (AMR)

AF:

0.00221

AC:

AN:

43844

Ashkenazi Jewish (ASJ)

AF:

0.00693

AC:

175

AN:

25238

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39432

South Asian (SAS)

AF:

0.000711

AC:

AN:

85810

European-Finnish (FIN)

AF:

0.00479

AC:

248

AN:

51760

Middle Eastern (MID)

AF:

0.00410

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00460

AC:

4993

AN:

1085330

Other (OTH)

AF:

0.00401

AC:

237

AN:

59056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

347

694

1040

1387

1734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00247

AC:

359

AN:

145132

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

186

AN XY:

70892

show subpopulations

African (AFR)

AF:

0.000758

AC:

AN:

39578

American (AMR)

AF:

0.00239

AC:

AN:

14646

Ashkenazi Jewish (ASJ)

AF:

0.00699

AC:

AN:

3290

East Asian (EAS)

AF:

0.00

AC:

AN:

4972

South Asian (SAS)

AF:

0.000220

AC:

AN:

4550

European-Finnish (FIN)

AF:

0.00441

AC:

AN:

9760

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00333

AC:

217

AN:

65142

Other (OTH)

AF:

0.000972

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.0116

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Factor VII deficiency (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.8

(source)

DANN

Benign

0.42

PhyloP100

0.87

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0019

dbscSNV1_RF

Benign

0.046

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over