1-196651811-C-T

Variant names:

• chr1-196651811-C-T
• rs74842824
• ENST00000359637.3:c.-307C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000359637.3(CFH):​c.-307C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 403,334 control chromosomes in the GnomAD database, including 36 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 0.0077 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (25 hom.)
• Consequence: CFH ENST00000359637.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.427
• Publications: 2 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=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1176/152252) while in subpopulation NFE AF = 0.0114 (777/67990). AF 95% confidence interval is 0.0108. There are 11 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Unknown,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.-307C>T		upstream_gene_variant		ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.-307C>T		upstream_gene_variant			NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.-307C>T		upstream_gene_variant		1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.-307C>T		upstream_gene_variant				ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152134 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00941 AC: 2362 AN: 251082 Hom.: 25 AF XY: 0.00877 AC XY: 1171 AN XY: 133470

African (AFR) AF: 0.00246 AC: 20 AN: 8134

American (AMR) AF: 0.00853 AC: 88 AN: 10322

Ashkenazi Jewish (ASJ) AF: 0.0339 AC: 260 AN: 7672

East Asian (EAS) AF: 0.00 AC: 0 AN: 15394

South Asian (SAS) AF: 0.00105 AC: 33 AN: 31384

European-Finnish (FIN) AF: 0.00399 AC: 46 AN: 11528

Middle Eastern (MID) AF: 0.0104 AC: 11 AN: 1060

European-Non Finnish (NFE) AF: 0.0117 AC: 1764 AN: 151122

Other (OTH) AF: 0.00968 AC: 140 AN: 14466

GnomAD4 genome AF: 0.00772 AC: 1176 AN: 152252 Hom.: 11 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74434

African (AFR) AF: 0.00245 AC: 102 AN: 41556

American (AMR) AF: 0.0102 AC: 156 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 67990

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0103 Hom.: 13

Bravo AF: 0.00832

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFH: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		-0.43
PromoterAI		-0.15	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74842824; hg19: chr1-196620941;