rs6680396

chr1-196663340-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000186.4(CFH):c.59-9638A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,980 control chromosomes in the GnomAD database, including 4,029 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 0.22 (4029 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

Genes affected

CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFH	NM_000186.4	c.59-9638A>G		intron_variant		ENST00000367429.9
CFH	NM_001014975.3	c.59-9638A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFH	ENST00000367429.9	c.59-9638A>G		intron_variant		1	NM_000186.4	P2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33429 AN: 151864 Hom.: 4021 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.220 AC: 33459 AN: 151980 Hom.: 4029 Cov.: 32 AF XY: 0.225 AC XY: 16740 AN XY: 74284

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.223

Alfa AF: 0.197 Hom.: 2201

Bravo AF: 0.219

Asia WGS AF: 0.316 AC: 1094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.74
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs6680396; hg19: chr1-196632470;