rs3093248

Variant names:

• chr13-113118940-G-A
• rs3093248
• NM_019616.4:c.1267G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_019616.4(F7):​c.1267G>A​(p.Glu423Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,609,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: F7 NM_019616.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.11
• Publications: 3 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: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.31991 (below the threshold of 3.09). Trascript score misZ: 0.36088 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor VII deficiency, factor VII deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.028267652).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019616.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	NM_019616.4	MANE Select	c.1267G>A	p.Glu423Lys	missense	Exon 8 of 8	NP_062562.1
	F7	NM_000131.5		c.1333G>A	p.Glu445Lys	missense	Exon 9 of 9	NP_000122.1
	F7	NM_001267554.2		c.1081G>A	p.Glu361Lys	missense	Exon 6 of 6	NP_001254483.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	ENST00000346342.8	TSL:1 MANE Select	c.1267G>A	p.Glu423Lys	missense	Exon 8 of 8	ENSP00000329546.4
	F7	ENST00000375581.3	TSL:1	c.1333G>A	p.Glu445Lys	missense	Exon 9 of 9	ENSP00000364731.3
	F7	ENST00000541084.5	TSL:2	c.1081G>A	p.Glu361Lys	missense	Exon 6 of 6	ENSP00000442051.2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000257 AC: 63 AN: 245338 AF XY: 0.000187

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 180 AN: 1457420 Hom.: 1 Cov.: 33 AF XY: 0.000102 AC XY: 74 AN XY: 725140

African (AFR) AF: 0.00436 AC: 146 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49098

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111938

Other (OTH) AF: 0.000265 AC: 16 AN: 60352

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000914 AC XY: 68 AN XY: 74398

African (AFR) AF: 0.00354 AC: 147 AN: 41530

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

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

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00128

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000347 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Congenital factor VII deficiency;C1832662:Myocardial infarction, susceptibility to (1)
-	1	-	F7-related disorder (1)
-	1	-	Factor VII deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.31	N
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.45
Sift	Benign	0.11	T
Sift4G	Benign	0.63	T
Polyphen		0.035	B
Vest4		0.48
MVP		0.86
MPC		0.25
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.30
gMVP		0.62
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs3093248; hg19: chr13-113773254;