chr1-196702856-G-A

Variant names:

• chr1-196702856-G-A
• rs402056
• NM_000186.4:c.1337-10879G>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.1337-10879G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 151,230 control chromosomes in the GnomAD database, including 36,668 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 0.69 (36668 hom., cov: 30)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.69
• Publications: 6 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 (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1337-10879G>A		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.1337-10879G>A		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1337-10879G>A		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104221 AN: 151112 Hom.: 36628 Cov.: 30

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.670

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.703

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

GnomAD4 genome AF: 0.690 AC: 104314 AN: 151230 Hom.: 36668 Cov.: 30 AF XY: 0.692 AC XY: 51117 AN XY: 73888

African (AFR) AF: 0.784 AC: 32308 AN: 41184

American (AMR) AF: 0.759 AC: 11542 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2392 AN: 3466

East Asian (EAS) AF: 0.948 AC: 4827 AN: 5094

South Asian (SAS) AF: 0.719 AC: 3442 AN: 4790

European-Finnish (FIN) AF: 0.559 AC: 5829 AN: 10426

Middle Eastern (MID) AF: 0.662 AC: 192 AN: 290

European-Non Finnish (NFE) AF: 0.617 AC: 41844 AN: 67774

Other (OTH) AF: 0.702 AC: 1476 AN: 2102

Alfa AF: 0.657 Hom.: 4153

Bravo AF: 0.713

Asia WGS AF: 0.792 AC: 2755 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	0.10
DANN	Benign	0.15
PhyloP100		-5.7
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: rs402056; hg19: chr1-196671986;