rs6046

Variant names:

• chr13-113118845-G-A
• rs6046
• NM_019616.4:c.1172G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-113118845-G-A
• chr13-113118845-G-C
• chr13-113118845-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BA1

The NM_019616.4(F7):​c.1172G>A​(p.Arg391Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,612,500 control chromosomes in the GnomAD database, including 12,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1175 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11745 hom.)
• Consequence: F7 NM_019616.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:6 O:1
• Conservation: PhyloP100: -0.0900
• Publications: 111 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: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_019616.4
• 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=0.003981173).
• BP6: Variant 13-113118845-G-A is Benign according to our data. Variant chr13-113118845-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12080.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

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.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	NP_062562.1	P08709-2
	F7	NM_000131.5		c.1238G>A	p.Arg413Gln	missense	Exon 9 of 9	NP_000122.1
	F7	NM_001267554.2		c.986G>A	p.Arg329Gln	missense	Exon 6 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.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	ENSP00000329546.4	P08709-2
	F7	ENST00000375581.3	TSL:1	c.1238G>A	p.Arg413Gln	missense	Exon 9 of 9	ENSP00000364731.3	P08709-1
	F7	ENST00000891255.1		c.1385G>A	p.Arg462Gln	missense	Exon 9 of 9	ENSP00000561314.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17693 AN: 152072 Hom.: 1172 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.0697

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.129 AC: 32014 AN: 247448 AF XY: 0.138

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.116 AC: 170074 AN: 1460312 Hom.: 11745 Cov.: 33 AF XY: 0.122 AC XY: 88822 AN XY: 726428

African (AFR) AF: 0.122 AC: 4101 AN: 33480

American (AMR) AF: 0.107 AC: 4795 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4992 AN: 26122

East Asian (EAS) AF: 0.0599 AC: 2378 AN: 39674

South Asian (SAS) AF: 0.276 AC: 23810 AN: 86228

European-Finnish (FIN) AF: 0.0736 AC: 3839 AN: 52184

Middle Eastern (MID) AF: 0.213 AC: 1231 AN: 5766

European-Non Finnish (NFE) AF: 0.106 AC: 117449 AN: 1111840

Other (OTH) AF: 0.124 AC: 7479 AN: 60358

GnomAD4 genome AF: 0.116 AC: 17700 AN: 152188 Hom.: 1175 Cov.: 33 AF XY: 0.116 AC XY: 8666 AN XY: 74410

African (AFR) AF: 0.121 AC: 5024 AN: 41532

American (AMR) AF: 0.116 AC: 1771 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3468

East Asian (EAS) AF: 0.0477 AC: 247 AN: 5174

South Asian (SAS) AF: 0.274 AC: 1322 AN: 4824

European-Finnish (FIN) AF: 0.0697 AC: 740 AN: 10614

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7396 AN: 67974

Other (OTH) AF: 0.132 AC: 277 AN: 2104

Alfa AF: 0.118 Hom.: 2395

Bravo AF: 0.119

TwinsUK AF: 0.114 AC: 423

ALSPAC AF: 0.100 AC: 387

ESP6500AA AF: 0.117 AC: 516

ESP6500EA AF: 0.106 AC: 914

ExAC AF: 0.131 AC: 15853

Asia WGS AF: 0.156 AC: 543 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.126

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Factor VII deficiency (1)
-	-	1	Factor X deficiency (1)
-	-	-	Myocardial infarction, decreased susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.9
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		-0.090
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Polyphen		0.25	B
Vest4		0.085
MPC		0.22
ClinPred		0.0032	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.42
Mutation Taster		=93/7	polymorphism (auto)

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: rs6046; hg19: chr13-113773159; COSMIC: COSV60645023; COSMIC: COSV60645023;