chr13-113106865-G-C

Variant names:

• chr13-113106865-G-C
• rs371824980
• ENST00000375581.3:c.85G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000131.5(F7):​c.85G>C​(p.Gly29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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 Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: F7 NM_000131.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 0 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), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine
• factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: 0.24236 (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=0.21003819).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	NM_019616.4	MANE Select	c.64+960G>C		intron	N/A	NP_062562.1	P08709-2
	F7	NM_000131.5		c.85G>C	p.Gly29Arg	missense	Exon 2 of 9	NP_000122.1
	F7	NM_001267554.2		c.64+960G>C		intron	N/A	NP_001254483.1	F5H8B0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	ENST00000375581.3	TSL:1	c.85G>C	p.Gly29Arg	missense	Exon 2 of 9	ENSP00000364731.3	P08709-1
	F7	ENST00000346342.8	TSL:1 MANE Select	c.64+960G>C		intron	N/A	ENSP00000329546.4	P08709-2
	F7	ENST00000891251.1		c.85G>C	p.Gly29Arg	missense	Exon 2 of 10	ENSP00000561310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722556

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108534

Other (OTH) AF: 0.00 AC: 0 AN: 60006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	3.2
DANN	Uncertain	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.050
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.22
Sift	Benign	0.063	T
Sift4G	Uncertain	0.033	D
Polyphen		0.98	D
Vest4		0.22
MutPred		0.32		Gain of MoRF binding (P = 0.0168)
MVP		0.94
MPC		0.29
ClinPred		0.17	T
GERP RS		0.50
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.064
gMVP		0.60
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371824980; hg19: chr13-113761179;