NM_000204.5:c.1149-993C>T

Variant names:

• chr4-109747495-G-A
• rs7438961
• NM_000204.5:c.1149-993C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000204.5(CFI):​c.1149-993C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 152,002 control chromosomes in the GnomAD database, including 24,786 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (24786 hom., cov: 32)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 7 publications found

Genes affected

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]

CFI Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome with I factor anomaly

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor I deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• age related macular degeneration 13

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285330 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.1149-993C>T		intron_variant	Intron 10 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.1149-993C>T		intron_variant	Intron 10 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.1149-993C>T		intron_variant	Intron 10 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82391 AN: 151886 Hom.: 24784 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.570

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.542 AC: 82404 AN: 152002 Hom.: 24786 Cov.: 32 AF XY: 0.542 AC XY: 40264 AN XY: 74290

African (AFR) AF: 0.269 AC: 11136 AN: 41468

American (AMR) AF: 0.546 AC: 8332 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2226 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2722 AN: 5162

South Asian (SAS) AF: 0.601 AC: 2894 AN: 4818

European-Finnish (FIN) AF: 0.638 AC: 6722 AN: 10530

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46518 AN: 67972

Other (OTH) AF: 0.572 AC: 1207 AN: 2110

Alfa AF: 0.628 Hom.: 87956

Bravo AF: 0.523

Asia WGS AF: 0.521 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.70
PhyloP100		-0.030
Mutation Taster		=100/0	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: rs7438961; hg19: chr4-110668651;