1-196701709-A-G

Variant names:

• chr1-196701709-A-G
• rs10754199
• NM_000186.4:c.1336+11470A>G

Variant summary

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

The NM_000186.4(CFH):​c.1336+11470A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 235,988 control chromosomes in the GnomAD database, including 49,440 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 0.65 (32307 hom., cov: 31)
  • Exomes 𝑓: 0.63 (17133 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 19 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 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.1336+11470A>G		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.*378A>G		downstream_gene	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.1336+11470A>G		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.1336+11470A>G		intron	N/A	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.3352+11470A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98297 AN: 151786 Hom.: 32284 Cov.: 31

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.626 AC: 52614 AN: 84084 Hom.: 17133 AF XY: 0.629 AC XY: 27602 AN XY: 43886

African (AFR) AF: 0.605 AC: 1900 AN: 3138

American (AMR) AF: 0.766 AC: 3278 AN: 4280

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 1371 AN: 2242

East Asian (EAS) AF: 0.940 AC: 3963 AN: 4216

South Asian (SAS) AF: 0.654 AC: 6755 AN: 10326

European-Finnish (FIN) AF: 0.539 AC: 1948 AN: 3614

Middle Eastern (MID) AF: 0.572 AC: 191 AN: 334

European-Non Finnish (NFE) AF: 0.590 AC: 30286 AN: 51312

Other (OTH) AF: 0.632 AC: 2922 AN: 4622

GnomAD4 genome AF: 0.648 AC: 98363 AN: 151904 Hom.: 32307 Cov.: 31 AF XY: 0.651 AC XY: 48302 AN XY: 74228

African (AFR) AF: 0.640 AC: 26499 AN: 41414

American (AMR) AF: 0.740 AC: 11294 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2298 AN: 3470

East Asian (EAS) AF: 0.948 AC: 4859 AN: 5126

South Asian (SAS) AF: 0.719 AC: 3463 AN: 4818

European-Finnish (FIN) AF: 0.562 AC: 5933 AN: 10556

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41943 AN: 67948

Other (OTH) AF: 0.668 AC: 1406 AN: 2106

Alfa AF: 0.632 Hom.: 39635

Bravo AF: 0.664

Asia WGS AF: 0.781 AC: 2716 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	3.6
DANN	Benign	0.40
PhyloP100		-0.58
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: rs10754199; hg19: chr1-196670839;