rs121964912

Variant names:

• chr4-109746398-T-A
• rs121964912
• NM_000204.5:c.1253A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-109746398-T-A
• chr4-109746398-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_000204.5(CFI):​c.1253A>T​(p.His418Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000417 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV006558268: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:19065647" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: CFI NM_000204.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.94
• Publications: 14 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
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Doyne honeycomb retinal dystrophy

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

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

ENSG00000285330 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006558268: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:19065647;32510551).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 4-109746398-T-A is Pathogenic according to our data. Variant chr4-109746398-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12118.

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.1253A>T	p.His418Leu	missense	Exon 11 of 13	NP_000195.3	P05156
	CFI	NM_001375278.1		c.1277A>T	p.His426Leu	missense	Exon 12 of 15	NP_001362207.1
	CFI	NM_001440985.1		c.1274A>T	p.His425Leu	missense	Exon 12 of 15	NP_001427914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.1253A>T	p.His418Leu	missense	Exon 11 of 13	ENSP00000378130.2	P05156
	ENSG00000285330	ENST00000645635.1		c.1253A>T	p.His418Leu	missense	Exon 11 of 15	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000963332.1		c.1343A>T	p.His448Leu	missense	Exon 12 of 14	ENSP00000633391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251376 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1112002

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	CFI-related disorder (1)
1	-	-	Factor I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.97
MPC		0.46
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121964912; hg19: chr4-110667554;