Genetic Variant CFH:c.245-10_245-9dupTT (chr1-196673839-C-CTT) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000186.4(CFH):c.245-10_245-9dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,480,524 control chromosomes in the GnomAD database, including 29,687 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4702 hom., cov: 23)

Exomes 𝑓: 0.23 ( 24985 hom. )

Consequence

CFH
NM_000186.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0950

Variant links:

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 links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-196673839-C-CTT is Benign according to our data. Variant chr1-196673839-C-CTT is described in ClinVar as [Benign]. Clinvar id is 1166414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.245-10_245-9dupTT		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000367429.9	NP_000177.2	P08603A0A024R962
CFH	NM_001014975.3 link	c.245-10_245-9dupTT		splice_region_variant, intron_variant	Intron 2 of 9		NP_001014975.1	A0A0D9SG88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.245-10_245-9dupTT		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 link	c.245-10_245-9dupTT		splice_region_variant, intron_variant	Intron 2 of 26			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36634

AN:

150994

Hom.:

4684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.293

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.496

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.244

GnomAD4 exome

AF:

0.226

AC:

300352

AN:

1329416

Hom.:

24985

Cov.:

AF XY:

0.228

AC XY:

152069

AN XY:

667864

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.429

Gnomad4 SAS exome

AF:

0.285

Gnomad4 FIN exome

AF:

0.270

Gnomad4 NFE exome

AF:

0.210

Gnomad4 OTH exome

AF:

0.227

GnomAD4 genome

AF:

0.243

AC:

36700

AN:

151108

Hom.:

4702

Cov.:

AF XY:

0.249

AC XY:

18396

AN XY:

73738

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.314

Gnomad4 ASJ

AF:

0.266

Gnomad4 EAS

AF:

0.496

Gnomad4 SAS

AF:

0.329

Gnomad4 FIN

AF:

0.281

Gnomad4 NFE

AF:

0.228

Gnomad4 OTH

AF:

0.247

Bravo

AF:

0.243

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 29, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor H deficiency

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atypical hemolytic-uremic syndrome

Benign:1

Dec 30, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Basal laminar drusen

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 4

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over