1-196673839-CTT-CTTTT

Position:

• chr1-196673839-CTT-CTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0950

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]

ENSG00000289697 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.245-10_245-9dupTT		splice_region_variant, intron_variant		ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.245-10_245-9dupTT		splice_region_variant, intron_variant			NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.245-10_245-9dupTT		splice_region_variant, intron_variant		1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.245-10_245-9dupTT		splice_region_variant, intron_variant				ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36634 AN: 150994 Hom.: 4684 Cov.: 23

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.: 25 AF XY: 0.228 AC XY: 152069 AN XY: 667864

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.: 23 AF XY: 0.249 AC XY: 18396 AN XY: 73738

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

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Factor H deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 30, 2020

- -

Basal laminar drusen Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Age related macular degeneration 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35507625; hg19: chr1-196642969;