rs1065489

Variant names:

• chr1-196740644-G-T
• rs1065489
• NM_000186.4:c.2808G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000186.4(CFH):​c.2808G>T​(p.Glu936Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,926 control chromosomes in the GnomAD database, including 29,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2412 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26716 hom.)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9297004E-4).
• BP6: Variant 1-196740644-G-T is Benign according to our data. Variant chr1-196740644-G-T is described in ClinVar as [Benign]. Clinvar id is 294509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196740644-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2808G>T	p.Glu936Asp	missense_variant	Exon 18 of 22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2808G>T	p.Glu936Asp	missense_variant	Exon 18 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2808G>T	p.Glu936Asp	missense_variant	Exon 18 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23280 AN: 151646 Hom.: 2412 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.205 AC: 51398 AN: 251208 Hom.: 7018 AF XY: 0.196 AC XY: 26649 AN XY: 135750

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.178 AC: 260579 AN: 1461162 Hom.: 26716 Cov.: 34 AF XY: 0.176 AC XY: 128199 AN XY: 726902

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.153 AC: 23273 AN: 151764 Hom.: 2412 Cov.: 32 AF XY: 0.154 AC XY: 11434 AN XY: 74128

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.158

Alfa AF: 0.167 Hom.: 4439

Bravo AF: 0.161

TwinsUK AF: 0.165 AC: 612

ALSPAC AF: 0.170 AC: 656

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.175 AC: 1503

ExAC AF: 0.196 AC: 23731

Asia WGS AF: 0.234 AC: 814 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.175

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31428128, 28173125, 14583443, 22790979, 20694013, 21868097, 18421087, 23660864, 25087612, 22718493) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

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

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

- -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Basal laminar drusen Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 4 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 22, 2021

Genome-Nilou Lab

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

Jan 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor H deficiency Benign:1

Jul 22, 2021

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Focal segmental glomerulosclerosis Benign:1

Sep 27, 2022

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.020
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.094
Sift	Benign	0.59	T
Sift4G	Benign	0.48	T
Vest4		0.067
MutPred		0.53		Loss of glycosylation at S938 (P = 0.1269);
MPC		0.20
ClinPred		0.0067	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1065489; hg19: chr1-196709774; COSMIC: COSV66405884;