rs551

Variant names:

• chr4-109740781-G-A
• rs551
• NM_000204.5:c.*112C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-109740781-G-A
• chr4-109740781-G-C
• chr4-109740781-G-T

Variant summary

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

The NM_000204.5(CFI):​c.*112C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 976,168 control chromosomes in the GnomAD database, including 477,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69571 hom., cov: 33)
  • Exomes 𝑓: 0.99 (407695 hom.)
• Consequence: CFI NM_000204.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.456
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-109740781-G-A is Benign according to our data. Variant chr4-109740781-G-A is described in ClinVar as Benign. ClinVar VariationId is 347143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000204.5. 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
	CFI	NM_000204.5	MANE Select	c.*112C>T		3_prime_UTR	Exon 13 of 13	NP_000195.3
	CFI	NM_001318057.2		c.*112C>T		3_prime_UTR	Exon 14 of 14	NP_001304986.2
	CFI	NM_001440986.1		c.*112C>T		3_prime_UTR	Exon 14 of 14	NP_001427915.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.*112C>T		3_prime_UTR	Exon 13 of 13	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.1534+1710C>T		intron	N/A	ENSP00000493607.1
	CFI	ENST00000963332.1		c.*112C>T		3_prime_UTR	Exon 14 of 14	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.953 AC: 145054 AN: 152196 Hom.: 69515 Cov.: 33

Gnomad AFR AF: 0.837

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.965

GnomAD2 exomes AF: 0.989 AC: 177694 AN: 179620 AF XY: 0.992

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.991

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.995 AC: 819323 AN: 823854 Hom.: 407695 Cov.: 11 AF XY: 0.995 AC XY: 429548 AN XY: 431490

African (AFR) AF: 0.839 AC: 17118 AN: 20398

American (AMR) AF: 0.990 AC: 36369 AN: 36748

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 21715 AN: 21718

East Asian (EAS) AF: 1.00 AC: 34558 AN: 34558

South Asian (SAS) AF: 1.00 AC: 69165 AN: 69182

European-Finnish (FIN) AF: 1.00 AC: 41444 AN: 41444

Middle Eastern (MID) AF: 0.980 AC: 4447 AN: 4538

European-Non Finnish (NFE) AF: 1.00 AC: 555642 AN: 555906

Other (OTH) AF: 0.987 AC: 38865 AN: 39362

GnomAD4 genome AF: 0.953 AC: 145166 AN: 152314 Hom.: 69571 Cov.: 33 AF XY: 0.955 AC XY: 71108 AN XY: 74478

African (AFR) AF: 0.837 AC: 34778 AN: 41526

American (AMR) AF: 0.982 AC: 15036 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5192 AN: 5192

South Asian (SAS) AF: 1.00 AC: 4825 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10627 AN: 10628

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67994 AN: 68044

Other (OTH) AF: 0.965 AC: 2040 AN: 2114

Alfa AF: 0.985 Hom.: 83745

Bravo AF: 0.947

Asia WGS AF: 0.989 AC: 3439 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome with I factor anomaly (1)
-	-	1	Factor I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.33
PhyloP100		-0.46
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: rs551; hg19: chr4-110661937;