rs800292

chr1-196673103-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000186.4(CFH):c.184G>A(p.Val62Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,612,358 control chromosomes in the GnomAD database, including 70,983 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (15198 hom., cov: 31)
  • Exomes 𝑓: 0.26 (55785 hom.)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:2
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a disulfide_bond (size 28) in uniprot entity CFAH_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000186.4
• BP4: Computational evidence support a benign effect (MetaRNN=5.604542E-6).
• BP6: Variant 1-196673103-G-A is Benign according to our data. Variant chr1-196673103-G-A is described in ClinVar as [Benign]. Clinvar id is 16550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196673103-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFH	NM_000186.4	c.184G>A	p.Val62Ile	missense_variant	2/22	ENST00000367429.9
CFH	NM_001014975.3	c.184G>A	p.Val62Ile	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFH	ENST00000367429.9	c.184G>A	p.Val62Ile	missense_variant	2/22	1	NM_000186.4	P2

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60251 AN: 151828 Hom.: 15151 Cov.: 31

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.317 AC: 79518 AN: 250544 Hom.: 14648 AF XY: 0.305 AC XY: 41348 AN XY: 135430

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.421

Gnomad SAS exome AF: 0.314

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.261 AC: 381288 AN: 1460412 Hom.: 55785 Cov.: 34 AF XY: 0.261 AC XY: 189294 AN XY: 726594

Gnomad4 AFR exome AF: 0.734

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.397 AC: 60366 AN: 151946 Hom.: 15198 Cov.: 31 AF XY: 0.399 AC XY: 29600 AN XY: 74264

Gnomad4 AFR AF: 0.716

Gnomad4 AMR AF: 0.389

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.357

Alfa AF: 0.253 Hom.: 14695

Bravo AF: 0.417

TwinsUK AF: 0.234 AC: 866

ALSPAC AF: 0.226 AC: 872

ESP6500AA AF: 0.708 AC: 3119

ESP6500EA AF: 0.222 AC: 1909

ExAC AF: 0.320 AC: 38882

Asia WGS AF: 0.432 AC: 1502 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.231

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Basal laminar drusen Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	not provided	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21106043, 25087612, 20538655, 23274582, 18340363, 19549636, 18421087, 20574013, 24722444, 21270465, 24550392, 22509112, 23441108, 20132989, 19187823, 21397333, 21555552, 16299065, 29686068, 28173125) -

Age related macular degeneration 4 Benign:2 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Sep 11, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Factor H deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.087
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.36	T;T;T
MetaRNN	Benign	0.0000056	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.49	N;.;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.10
MPC		0.11
ClinPred		0.0013	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs800292; hg19: chr1-196642233; COSMIC: COSV62776782; COSMIC: COSV62776782;