19-860852-G-C

Variant names:

• chr19-860852-G-C
• rs1629038
• NM_001928.4:c.213-9G>C

Variant summary

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

The NM_001928.4(CFD):​c.213-9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,563,062 control chromosomes in the GnomAD database, including 250,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20334 hom., cov: 29)
  • Exomes 𝑓: 0.57 (229763 hom.)
• Consequence: CFD NM_001928.4 intron
• Scores: Splicing: ADA: 0.00001004
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.435
• Publications: 14 publications found

Genes affected

CFD (HGNC:2771): (complement factor D) This gene encodes a member of the S1, or chymotrypsin, family of serine peptidases. This protease catalyzes the cleavage of factor B, the rate-limiting step of the alternative pathway of complement activation. This protein also functions as an adipokine, a cell signaling protein secreted by adipocytes, which regulates insulin secretion in mice. Mutations in this gene underlie complement factor D deficiency, which is associated with recurrent bacterial meningitis infections in human patients. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protease. [provided by RefSeq, Nov 2015]

CFD Gene-Disease associations (from GenCC):

• recurrent Neisseria infections due to factor D deficiency

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-860852-G-C is Benign according to our data. Variant chr19-860852-G-C is described in ClinVar as Benign. ClinVar VariationId is 402532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001928.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	NM_001928.4	MANE Select	c.213-9G>C		intron	N/A	NP_001919.2
	CFD	NM_001317335.2		c.234-9G>C		intron	N/A	NP_001304264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	ENST00000327726.11	TSL:1 MANE Select	c.213-9G>C		intron	N/A	ENSP00000332139.4
	CFD	ENST00000592860.3	TSL:1	c.234-9G>C		intron	N/A	ENSP00000468253.1
	CFD	ENST00000695945.1		c.213-9G>C		intron	N/A	ENSP00000512278.1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77131 AN: 151406 Hom.: 20331 Cov.: 29

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.496

GnomAD2 exomes AF: 0.519 AC: 86417 AN: 166666 AF XY: 0.527

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.577

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.549

GnomAD4 exome AF: 0.566 AC: 798983 AN: 1411540 Hom.: 229763 Cov.: 65 AF XY: 0.566 AC XY: 395604 AN XY: 699450

African (AFR) AF: 0.387 AC: 12584 AN: 32522

American (AMR) AF: 0.440 AC: 16961 AN: 38538

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 14733 AN: 25396

East Asian (EAS) AF: 0.302 AC: 11218 AN: 37148

South Asian (SAS) AF: 0.539 AC: 44134 AN: 81926

European-Finnish (FIN) AF: 0.656 AC: 25404 AN: 38718

Middle Eastern (MID) AF: 0.419 AC: 2293 AN: 5472

European-Non Finnish (NFE) AF: 0.585 AC: 639308 AN: 1093076

Other (OTH) AF: 0.551 AC: 32348 AN: 58744

GnomAD4 genome AF: 0.509 AC: 77156 AN: 151522 Hom.: 20334 Cov.: 29 AF XY: 0.510 AC XY: 37749 AN XY: 74032

African (AFR) AF: 0.392 AC: 16178 AN: 41296

American (AMR) AF: 0.477 AC: 7273 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1520 AN: 5106

South Asian (SAS) AF: 0.517 AC: 2487 AN: 4812

European-Finnish (FIN) AF: 0.652 AC: 6868 AN: 10532

Middle Eastern (MID) AF: 0.424 AC: 123 AN: 290

European-Non Finnish (NFE) AF: 0.576 AC: 39037 AN: 67746

Other (OTH) AF: 0.490 AC: 1029 AN: 2102

Alfa AF: 0.548 Hom.: 4696

Bravo AF: 0.493

Asia WGS AF: 0.437 AC: 1521 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.54
PhyloP100		-0.43
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
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

Other links and lift over

dbSNP: rs1629038; hg19: chr19-860852; COSMIC: COSV55048218; COSMIC: COSV55048218;