NM_000186.4:c.59-7002G>A

Variant names:

• chr1-196665976-G-A
• rs529825
• NM_000186.4:c.59-7002G>A

Variant summary

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

The NM_000186.4(CFH):​c.59-7002G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,070 control chromosomes in the GnomAD database, including 15,059 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 0.40 (15059 hom., cov: 33)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• Publications: 21 publications found

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]

CFH Gene-Disease associations (from GenCC):

• primary membranoproliferative glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• basal laminar drusen

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dense deposit disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. 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
	CFH	NM_000186.4	MANE Select	c.59-7002G>A		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.59-7002G>A		intron	N/A	NP_001014975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.59-7002G>A		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.59-7002G>A		intron	N/A	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.59-7002G>A		intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59976 AN: 151952 Hom.: 15011 Cov.: 33

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.395 AC: 60091 AN: 152070 Hom.: 15059 Cov.: 33 AF XY: 0.396 AC XY: 29423 AN XY: 74346

African (AFR) AF: 0.712 AC: 29554 AN: 41490

American (AMR) AF: 0.389 AC: 5945 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3464

East Asian (EAS) AF: 0.409 AC: 2108 AN: 5154

South Asian (SAS) AF: 0.308 AC: 1485 AN: 4826

European-Finnish (FIN) AF: 0.297 AC: 3141 AN: 10572

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15854 AN: 67972

Other (OTH) AF: 0.356 AC: 751 AN: 2110

Alfa AF: 0.297 Hom.: 6732

Bravo AF: 0.416

Asia WGS AF: 0.429 AC: 1489 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs529825; hg19: chr1-196635106;