ENST00000695946.1:c.259-1594T>C

Variant names:

• chr19-865835-T-C
• rs1651896
• ENST00000695946.1:c.259-1594T>C

Variant summary

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

The ENST00000695946.1(CFD):​c.259-1594T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 152,046 control chromosomes in the GnomAD database, including 39,471 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 0.71 (39471 hom., cov: 32)
• Consequence: CFD ENST00000695946.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000695946.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	ENST00000695946.1		c.259-1594T>C		intron	N/A	ENSP00000512279.1

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108327 AN: 151928 Hom.: 39411 Cov.: 32

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.717

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

GnomAD4 genome AF: 0.713 AC: 108441 AN: 152046 Hom.: 39471 Cov.: 32 AF XY: 0.708 AC XY: 52625 AN XY: 74334

African (AFR) AF: 0.856 AC: 35503 AN: 41482

American (AMR) AF: 0.610 AC: 9300 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2232 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3154 AN: 5160

South Asian (SAS) AF: 0.699 AC: 3375 AN: 4828

European-Finnish (FIN) AF: 0.606 AC: 6395 AN: 10560

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46277 AN: 67974

Other (OTH) AF: 0.721 AC: 1520 AN: 2108

Alfa AF: 0.700 Hom.: 63085

Bravo AF: 0.717

Asia WGS AF: 0.652 AC: 2264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.22
PhyloP100		-0.98

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1651896; hg19: chr19-865835;