1-196727745-G-T

Variant names:

• chr1-196727745-G-T
• rs419137
• NM_000186.4:c.2237-601G>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.2237-601G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 152,214 control chromosomes in the GnomAD database, including 64,886 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 0.92 (64886 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.44
• Publications: 18 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2237-601G>T		intron_variant	Intron 14 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2237-601G>T		intron_variant	Intron 14 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2237-601G>T		intron_variant	Intron 14 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140219 AN: 152096 Hom.: 64829 Cov.: 32

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.947

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.923

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

GnomAD4 genome AF: 0.922 AC: 140333 AN: 152214 Hom.: 64886 Cov.: 32 AF XY: 0.924 AC XY: 68783 AN XY: 74402

African (AFR) AF: 0.979 AC: 40695 AN: 41570

American (AMR) AF: 0.947 AC: 14469 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3245 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5168

South Asian (SAS) AF: 0.933 AC: 4501 AN: 4822

European-Finnish (FIN) AF: 0.902 AC: 9548 AN: 10584

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59591 AN: 68004

Other (OTH) AF: 0.924 AC: 1951 AN: 2112

Alfa AF: 0.893 Hom.: 77003

Bravo AF: 0.929

Asia WGS AF: 0.969 AC: 3368 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome Benign:1

Oct 02, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

CFH c.2237-601G>T is a deep intronic variant located in intron 14. This variant is present at high allele frequency in population databases. In conclusion, we classify CFH c.2237-601G>T as a benign variant.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.081
DANN	Benign	0.49
PhyloP100		-1.4
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: rs419137; hg19: chr1-196696875;