NM_000186.4:c.1337-7686G>C

Variant names:

• chr1-196706049-G-C
• rs1887973
• NM_000186.4:c.1337-7686G>C

Variant summary

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

The NM_000186.4(CFH):​c.1337-7686G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,686 control chromosomes in the GnomAD database, including 29,977 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 0.62 (29977 hom., cov: 29)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 8 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 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.1337-7686G>C		intron	N/A	NP_000177.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1337-7686G>C		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.1337-7686G>C		intron	N/A	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.3353-7686G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94448 AN: 151568 Hom.: 29954 Cov.: 29

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.648

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

GnomAD4 genome AF: 0.623 AC: 94514 AN: 151686 Hom.: 29977 Cov.: 29 AF XY: 0.628 AC XY: 46560 AN XY: 74096

African (AFR) AF: 0.634 AC: 26186 AN: 41322

American (AMR) AF: 0.723 AC: 11024 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2212 AN: 3466

East Asian (EAS) AF: 0.927 AC: 4770 AN: 5146

South Asian (SAS) AF: 0.706 AC: 3380 AN: 4786

European-Finnish (FIN) AF: 0.544 AC: 5726 AN: 10530

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39191 AN: 67880

Other (OTH) AF: 0.647 AC: 1364 AN: 2108

Alfa AF: 0.451 Hom.: 1163

Bravo AF: 0.641

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.25
DANN	Benign	0.57
PhyloP100		-0.27
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: rs1887973; hg19: chr1-196675179;