1-196654207-T-C

Variant names:

• chr1-196654207-T-C
• rs7524776
• NM_000186.4:c.58+2032T>C

Variant summary

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

The NM_000186.4(CFH):​c.58+2032T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,072 control chromosomes in the GnomAD database, including 1,798 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 0.15 (1798 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.58+2032T>C		intron_variant	Intron 1 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.58+2032T>C		intron_variant	Intron 1 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.58+2032T>C		intron_variant	Intron 1 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.58+2032T>C		intron_variant	Intron 1 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22835 AN: 151952 Hom.: 1792 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.150 AC: 22863 AN: 152072 Hom.: 1798 Cov.: 32 AF XY: 0.147 AC XY: 10950 AN XY: 74346

African (AFR) AF: 0.171 AC: 7084 AN: 41490

American (AMR) AF: 0.126 AC: 1918 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 660 AN: 3464

East Asian (EAS) AF: 0.0395 AC: 205 AN: 5184

South Asian (SAS) AF: 0.101 AC: 486 AN: 4830

European-Finnish (FIN) AF: 0.137 AC: 1452 AN: 10594

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10593 AN: 67912

Other (OTH) AF: 0.157 AC: 331 AN: 2110

Alfa AF: 0.152 Hom.: 7097

Bravo AF: 0.152

Asia WGS AF: 0.124 AC: 429 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.89
DANN	Benign	0.83
PhyloP100		-2.2
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: rs7524776; hg19: chr1-196623337;