rs203687

Variant names:

• chr1-196705140-C-T
• rs203687
• NM_000186.4:c.1337-8595C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000186.4(CFH):​c.1337-8595C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 152,066 control chromosomes in the GnomAD database, including 39,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.71 (39816 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.247
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 1-196705140-C-T is Benign according to our data. Variant chr1-196705140-C-T is described in ClinVar as Benign. ClinVar VariationId is 1712366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1337-8595C>T		intron_variant	Intron 9 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1337-8595C>T		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1337-8595C>T		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107368 AN: 151948 Hom.: 39760 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.712

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

GnomAD4 genome AF: 0.707 AC: 107479 AN: 152066 Hom.: 39816 Cov.: 32 AF XY: 0.709 AC XY: 52666 AN XY: 74304

African (AFR) AF: 0.914 AC: 37953 AN: 41508

American (AMR) AF: 0.760 AC: 11596 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2319 AN: 3470

East Asian (EAS) AF: 0.948 AC: 4901 AN: 5170

South Asian (SAS) AF: 0.710 AC: 3428 AN: 4830

European-Finnish (FIN) AF: 0.544 AC: 5726 AN: 10524

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39392 AN: 67982

Other (OTH) AF: 0.711 AC: 1502 AN: 2114

Alfa AF: 0.692 Hom.: 6689

Bravo AF: 0.735

Asia WGS AF: 0.795 AC: 2764 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kidney disorder Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.51
PhyloP100		-0.25
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: rs203687; hg19: chr1-196674270;