NM_019616.4:c.-122T>C

Variant names:

• chr13-113105720-T-C
• rs561241
• NM_019616.4:c.-122T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019616.4(F7):​c.-122T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,145,320 control chromosomes in the GnomAD database, including 10,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1257 hom., cov: 31)
  • Exomes 𝑓: 0.13 (9422 hom.)
• Consequence: F7 NM_019616.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• Publications: 48 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-113105720-T-C is Benign according to our data. Variant chr13-113105720-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4	c.-122T>C		upstream_gene_variant		ENST00000346342.8	NP_062562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F7	ENST00000346342.8	c.-122T>C		upstream_gene_variant		1	NM_019616.4	ENSP00000329546.4
F7	ENST00000375581.3	c.-122T>C		upstream_gene_variant		1		ENSP00000364731.3
F7	ENST00000541084.5	c.-122T>C		upstream_gene_variant		2		ENSP00000442051.2
F7	ENST00000444337.1	n.-122T>C		upstream_gene_variant		5		ENSP00000387669.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18803 AN: 152062 Hom.: 1256 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.0391

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.127 AC: 125838 AN: 993142 Hom.: 9422 AF XY: 0.133 AC XY: 66896 AN XY: 502786

African (AFR) AF: 0.135 AC: 3212 AN: 23864

American (AMR) AF: 0.119 AC: 4167 AN: 35060

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4135 AN: 22720

East Asian (EAS) AF: 0.0501 AC: 1686 AN: 33656

South Asian (SAS) AF: 0.271 AC: 19291 AN: 71084

European-Finnish (FIN) AF: 0.0785 AC: 2789 AN: 35524

Middle Eastern (MID) AF: 0.213 AC: 1027 AN: 4820

European-Non Finnish (NFE) AF: 0.116 AC: 83641 AN: 721684

Other (OTH) AF: 0.132 AC: 5890 AN: 44730

GnomAD4 genome AF: 0.124 AC: 18811 AN: 152178 Hom.: 1257 Cov.: 31 AF XY: 0.124 AC XY: 9225 AN XY: 74402

African (AFR) AF: 0.127 AC: 5291 AN: 41500

American (AMR) AF: 0.121 AC: 1854 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 668 AN: 3472

East Asian (EAS) AF: 0.0392 AC: 202 AN: 5158

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4822

European-Finnish (FIN) AF: 0.0758 AC: 804 AN: 10612

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8195 AN: 67998

Other (OTH) AF: 0.139 AC: 294 AN: 2110

Alfa AF: 0.111 Hom.: 690

Bravo AF: 0.126

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17292373) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.88
PhyloP100		-1.1
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs561241; hg19: chr13-113760034;