ENST00000645635.1:c.1534+1812A>G

Variant names:

• chr4-109740679-T-C
• rs28361433
• ENST00000645635.1:c.1534+1812A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000645635.1(ENSG00000285330):​c.1534+1812A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 602,858 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (235 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (98 hom.)
• Consequence: ENSG00000285330 ENST00000645635.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962

Genes affected

ENSG00000285330 (HGNC:):

CFI (HGNC:5394): (complement factor I) This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-109740679-T-C is Benign according to our data. Variant chr4-109740679-T-C is described in ClinVar as [Benign]. Clinvar id is 369434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.*214A>G		downstream_gene_variant		ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285330	ENST00000645635.1	c.1534+1812A>G		intron_variant	Intron 12 of 14			ENSP00000493607.1
CFI	ENST00000394634.7	c.*214A>G		downstream_gene_variant		1	NM_000204.5	ENSP00000378130.2

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4808 AN: 152192 Hom.: 235 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0105 AC: 1051 AN: 100392 Hom.: 49 AF XY: 0.00860 AC XY: 469 AN XY: 54536

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.000119

Gnomad SAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00926

GnomAD4 exome AF: 0.00599 AC: 2699 AN: 450548 Hom.: 98 Cov.: 4 AF XY: 0.00530 AC XY: 1294 AN XY: 244034

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0316 AC: 4814 AN: 152310 Hom.: 235 Cov.: 33 AF XY: 0.0305 AC XY: 2275 AN XY: 74482

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0241 Hom.: 28

Bravo AF: 0.0368

Asia WGS AF: 0.00780 AC: 28 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Atypical hemolytic-uremic syndrome with I factor anomaly Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28361433; hg19: chr4-110661835;