chr1-196737547-G-T

Variant names:

• chr1-196737547-G-T
• rs515299
• NM_000186.4:c.2669G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000186.4(CFH):​c.2669G>T​(p.Ser890Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,318 control chromosomes in the GnomAD database, including 1,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S890T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (844 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (758 hom.)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.46
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057353973).
• BP6: Variant 1-196737547-G-T is Benign according to our data. Variant chr1-196737547-G-T is described in ClinVar as Benign. ClinVar VariationId is 294507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.2669G>T	p.Ser890Ile	missense	Exon 17 of 22	NP_000177.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.2669G>T	p.Ser890Ile	missense	Exon 17 of 22	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.2669G>T	p.Ser890Ile	missense	Exon 17 of 27	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.4685G>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8906 AN: 152054 Hom.: 841 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0170 AC: 4258 AN: 251058 AF XY: 0.0129

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00980

GnomAD4 exome AF: 0.00703 AC: 10265 AN: 1461146 Hom.: 758 Cov.: 31 AF XY: 0.00631 AC XY: 4588 AN XY: 726892

African (AFR) AF: 0.203 AC: 6779 AN: 33434

American (AMR) AF: 0.0124 AC: 554 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 752 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5762

European-Non Finnish (NFE) AF: 0.000793 AC: 882 AN: 1111570

Other (OTH) AF: 0.0176 AC: 1061 AN: 60350

GnomAD4 genome AF: 0.0587 AC: 8936 AN: 152172 Hom.: 844 Cov.: 32 AF XY: 0.0569 AC XY: 4237 AN XY: 74416

African (AFR) AF: 0.199 AC: 8246 AN: 41490

American (AMR) AF: 0.0254 AC: 388 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 68008

Other (OTH) AF: 0.0445 AC: 94 AN: 2110

Alfa AF: 0.0230 Hom.: 986

Bravo AF: 0.0667

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.189 AC: 834

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.0198 AC: 2400

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15800115, 21881555, 24799305, 29888403, 30046676, 29686068, 23431077, 27884173, 20981092)

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Mar 06, 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.

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Basal laminar drusen Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 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.

Age related macular degeneration 4 Benign:2

Mar 06, 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.

Apr 11, 2023

Genome-Nilou Lab

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

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

Mar 06, 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

Jul 08, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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;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 p.Ser890Ile (c.2669G>T) is a missense variant that changes the amino acid at residue 890 from Serine to Isoleucine. This variant has been reported in the published literature (PMID:16621965;23982707;29888403;36445700;34508573;21881555). In silico models agree that this variant is not damaging. This variant is present at high allele frequency in population databases. In conclusion, we classify CFH p.Ser890Ile (c.2669G>T) as a benign variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.081
DANN	Benign	0.94
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
PhyloP100		-3.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.057
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Vest4		0.024
MPC		0.17
ClinPred		0.0013	T
GERP RS		-3.6
gMVP		0.72
Mutation Taster		=81/19	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: rs515299; hg19: chr1-196706677;