13-113105913-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019616.4(F7):c.64+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,581,356 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (20 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: F7 NM_019616.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005447
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.196

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-113105913-C-T is Benign according to our data. Variant chr13-113105913-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 311219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00918 (1395/151986) while in subpopulation AFR AF= 0.0325 (1345/41416). AF 95% confidence interval is 0.031. There are 20 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F7	NM_019616.4	c.64+8C>T		splice_region_variant, intron_variant		ENST00000346342.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F7	ENST00000346342.8	c.64+8C>T		splice_region_variant, intron_variant		1	NM_019616.4	P2
F7	ENST00000375581.3	c.64+8C>T		splice_region_variant, intron_variant		1		A2
F7	ENST00000541084.5	c.64+8C>T		splice_region_variant, intron_variant		2
F7	ENST00000444337.1	c.64+8C>T		splice_region_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1389 AN: 151868 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.0000147

Gnomad OTH AF: 0.00337

GnomAD3 exomes AF: 0.00243 AC: 491 AN: 202250 Hom.: 9 AF XY: 0.00179 AC XY: 194 AN XY: 108120

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000793

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00105 AC: 1506 AN: 1429370 Hom.: 27 Cov.: 31 AF XY: 0.000956 AC XY: 676 AN XY: 707208

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000613

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000766

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00918 AC: 1395 AN: 151986 Hom.: 20 Cov.: 31 AF XY: 0.00871 AC XY: 647 AN XY: 74290

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00474 Hom.: 3

Bravo AF: 0.0109

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Factor VII deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.5
Dann	Benign	0.50
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs10482844; hg19: chr13-113760227;