1-196701627-C-T

Variant names:

• chr1-196701627-C-T
• rs4658046
• NM_000186.4:c.1336+11388C>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.1336+11388C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 408,790 control chromosomes in the GnomAD database, including 88,619 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 (32309 hom., cov: 32)
  • Exomes 𝑓: 0.66 (56310 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 20 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):

• C3 glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• basal laminar drusen

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.1336+11388C>T		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.*296C>T		downstream_gene	N/A	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1336+11388C>T		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1336+11388C>T		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.3352+11388C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98328 AN: 151854 Hom.: 32287 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.667

GnomAD4 exome AF: 0.655 AC: 168299 AN: 256820 Hom.: 56310 AF XY: 0.658 AC XY: 88968 AN XY: 135304

African (AFR) AF: 0.643 AC: 5191 AN: 8068

American (AMR) AF: 0.785 AC: 8764 AN: 11164

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 5063 AN: 7840

East Asian (EAS) AF: 0.943 AC: 15491 AN: 16430

South Asian (SAS) AF: 0.689 AC: 19514 AN: 28320

European-Finnish (FIN) AF: 0.565 AC: 8282 AN: 14668

Middle Eastern (MID) AF: 0.612 AC: 682 AN: 1114

European-Non Finnish (NFE) AF: 0.619 AC: 95653 AN: 154490

Other (OTH) AF: 0.656 AC: 9659 AN: 14726

GnomAD4 genome AF: 0.647 AC: 98392 AN: 151970 Hom.: 32309 Cov.: 32 AF XY: 0.651 AC XY: 48330 AN XY: 74288

African (AFR) AF: 0.640 AC: 26512 AN: 41422

American (AMR) AF: 0.740 AC: 11302 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2296 AN: 3470

East Asian (EAS) AF: 0.948 AC: 4876 AN: 5146

South Asian (SAS) AF: 0.719 AC: 3458 AN: 4810

European-Finnish (FIN) AF: 0.562 AC: 5938 AN: 10572

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

European-Non Finnish (NFE) AF: 0.617 AC: 41936 AN: 67954

Other (OTH) AF: 0.666 AC: 1410 AN: 2116

Alfa AF: 0.630 Hom.: 4634

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	-0.98
CADD	Benign	0.10
DANN	Benign	0.58
PhyloP100		-1.8
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: rs4658046; hg19: chr1-196670757;