rs1629038

chr19-860852-G-C

Variant summary

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

The NM_001928.4(CFD):c.213-9G>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001004
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.435

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 402532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-860852-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFD	NM_001928.4	c.213-9G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000327726.11
CFD	NM_001317335.2	c.234-9G>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFD	ENST00000327726.11	c.213-9G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001928.4	P2

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

GnomAD3 exomes AF: 0.519 AC: 86417 AN: 166666 Hom.: 23070 AF XY: 0.527 AC XY: 48645 AN XY: 92294

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 SAS exome AF: 0.543

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

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.585

Gnomad4 OTH exome AF: 0.551

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

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.517

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.490

Alfa AF: 0.548 Hom.: 4696

Bravo AF: 0.493

Asia WGS AF: 0.437 AC: 1521 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.3
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

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