rs766294997

Variant names:

• chr13-113105843-T-A
• rs766294997
• NM_019616.4:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-113105843-T-A
• chr13-113105843-T-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_019616.4(F7):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,602 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: F7 NM_019616.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.953
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 60 pathogenic variants. Next in-frame start position is after 336 codons. Genomic position: 113118679. Lost 0.754 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	NM_019616.4	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 8	NP_062562.1	P08709-2
	F7	NM_000131.5		c.2T>A	p.Met1?	start_lost	Exon 1 of 9	NP_000122.1
	F7	NM_001267554.2		c.2T>A	p.Met1?	start_lost	Exon 1 of 6	NP_001254483.1	F5H8B0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	ENST00000346342.8	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000329546.4	P08709-2
	F7	ENST00000375581.3	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 9	ENSP00000364731.3	P08709-1
	F7	ENST00000891255.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 9	ENSP00000561314.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435602 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711172

⚠️ 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: 33358

American (AMR) AF: 0.00 AC: 0 AN: 40702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00 AC: 0 AN: 81878

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099590

Other (OTH) AF: 0.00 AC: 0 AN: 59540

⚠️ 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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.22	T
PhyloP100		0.95
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.85
MutPred		0.76		Loss of stability (P = 0.0191)
MVP		0.97
ClinPred		0.75	D
GERP RS		2.8
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.94
Mutation Taster		=13/187	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766294997; hg19: chr13-113760157;