1-196683704-C-T

Variant names:

• chr1-196683704-C-T
• rs16840422
• NM_000186.4:c.791-1360C>T

Variant summary

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

The NM_000186.4(CFH):​c.791-1360C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 151,626 control chromosomes in the GnomAD database, including 4,697 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 (4697 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 12 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 (AFR) allele frequency at 95% confidence interval = 0.4 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.791-1360C>T		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.791-1360C>T		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.791-1360C>T		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.791-1360C>T		intron	N/A	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.791-1360C>T		intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32683 AN: 151508 Hom.: 4696 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.216 AC: 32707 AN: 151626 Hom.: 4697 Cov.: 32 AF XY: 0.215 AC XY: 15938 AN XY: 74110

African (AFR) AF: 0.405 AC: 16749 AN: 41378

American (AMR) AF: 0.145 AC: 2197 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3458

East Asian (EAS) AF: 0.0780 AC: 402 AN: 5156

South Asian (SAS) AF: 0.260 AC: 1255 AN: 4820

European-Finnish (FIN) AF: 0.121 AC: 1278 AN: 10588

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9718 AN: 67730

Other (OTH) AF: 0.218 AC: 460 AN: 2108

Alfa AF: 0.145 Hom.: 1024

Bravo AF: 0.222

Asia WGS AF: 0.179 AC: 623 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.12
DANN	Benign	0.27
PhyloP100		-1.1
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: rs16840422; hg19: chr1-196652834;