1-196737512-C-T

Variant names:

• chr1-196737512-C-T
• rs35292876
• NM_000186.4:c.2634C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000186.4(CFH):​c.2634C>T​(p.His878His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,612,918 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (118 hom.)
• Consequence: CFH NM_000186.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.578

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-196737512-C-T is Benign according to our data. Variant chr1-196737512-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 294504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196737512-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.578 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00867 (1319/152192) while in subpopulation SAS AF= 0.0222 (107/4820). AF 95% confidence interval is 0.0188. There are 8 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2634C>T	p.His878His	synonymous_variant	Exon 17 of 22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2634C>T	p.His878His	synonymous_variant	Exon 17 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2634C>T	p.His878His	synonymous_variant	Exon 17 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1316 AN: 152074 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00756

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00984

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0104 AC: 2602 AN: 250892 Hom.: 24 AF XY: 0.0119 AC XY: 1617 AN XY: 135598

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.00608

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00882

GnomAD4 exome AF: 0.00986 AC: 14399 AN: 1460726 Hom.: 118 Cov.: 31 AF XY: 0.0108 AC XY: 7822 AN XY: 726684

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.00644

Gnomad4 ASJ exome AF: 0.00464

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0295

Gnomad4 FIN exome AF: 0.00687

Gnomad4 NFE exome AF: 0.00920

Gnomad4 OTH exome AF: 0.00941

GnomAD4 genome AF: 0.00867 AC: 1319 AN: 152192 Hom.: 8 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74404

Gnomad4 AFR AF: 0.00633

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.00756

Gnomad4 NFE AF: 0.00984

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0116 Hom.: 25

Bravo AF: 0.00800

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFH: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Basal laminar drusen Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 4 Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor H deficiency Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome Benign:1

Sep 14, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.6
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35292876; hg19: chr1-196706642; COSMIC: COSV66405515;