dbSNP rs121964936: F7:p.His386Gln (chr13-113118831-T-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM1PM2PM5PP3_Strong

The NM_019616.4(F7):c.1158T>A(p.His386Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H386R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.72

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 Pathogenic. Variant got 14 ACMG points.

PS1

Transcript NM_019616.4 (F7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 12088

PM1

In a helix (size 3) in uniprot entity FA7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_019616.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-113118830-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3575772.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4 link	c.1158T>A	p.His386Gln	missense_variant	Exon 8 of 8	ENST00000346342.8	NP_062562.1	P08709-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F7	ENST00000346342.8 link	c.1158T>A	p.His386Gln	missense_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 link	c.1224T>A	p.His408Gln	missense_variant	Exon 9 of 9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 link	c.972T>A	p.His324Gln	missense_variant	Exon 6 of 6	2		ENSP00000442051.2	F5H8B0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460520

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

2.5

DANN

Benign

0.90

DEOGEN2

Pathogenic

0.87

.;.;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

0.28

.;.;N

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.5

.;D;D

REVEL

Uncertain

0.53

Sift

Benign

0.049

.;D;D

Sift4G

Uncertain

0.046

D;T;T

Polyphen

1.0

.;D;D

Vest4

0.77

MutPred

0.78

.;.;Gain of catalytic residue at S404 (P = 0);

MVP

0.84

MPC

0.74

ClinPred

0.97

GERP RS

-5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over