NM_000186.4:c.184G>A

Variant names:

• chr1-196673103-G-A
• rs800292
• NM_000186.4:c.184G>A

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.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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:14 O:2
• Conservation: PhyloP100: 1.60
• Publications: 490 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=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 VariationId is 16550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.184G>A	p.Val62Ile	missense	Exon 2 of 22	NP_000177.2
	CFH	NM_001014975.3		c.184G>A	p.Val62Ile	missense	Exon 2 of 10	NP_001014975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.184G>A	p.Val62Ile	missense	Exon 2 of 22	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.184G>A	p.Val62Ile	missense	Exon 2 of 27	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.184G>A	p.Val62Ile	missense	Exon 2 of 10	ENSP00000487250.1

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

GnomAD2 exomes AF: 0.317 AC: 79518 AN: 250544 AF XY: 0.305

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 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

African (AFR) AF: 0.734 AC: 24551 AN: 33446

American (AMR) AF: 0.381 AC: 17038 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6898 AN: 26126

East Asian (EAS) AF: 0.415 AC: 16441 AN: 39658

South Asian (SAS) AF: 0.314 AC: 27066 AN: 86224

European-Finnish (FIN) AF: 0.296 AC: 15784 AN: 53400

Middle Eastern (MID) AF: 0.205 AC: 1181 AN: 5760

European-Non Finnish (NFE) AF: 0.230 AC: 255332 AN: 1110734

Other (OTH) AF: 0.282 AC: 16997 AN: 60342

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

African (AFR) AF: 0.716 AC: 29665 AN: 41424

American (AMR) AF: 0.389 AC: 5937 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3464

East Asian (EAS) AF: 0.423 AC: 2173 AN: 5136

South Asian (SAS) AF: 0.326 AC: 1571 AN: 4814

European-Finnish (FIN) AF: 0.296 AC: 3130 AN: 10572

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15888 AN: 67956

Other (OTH) AF: 0.357 AC: 752 AN: 2106

Alfa AF: 0.279 Hom.: 34897

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Basal laminar drusen (3)
-	-	3	not provided (4)
-	-	2	Age related macular degeneration 4 (3)
-	-	2	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (2)
-	-	1	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)
-	-	1	Factor H deficiency (1)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000056	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs800292; hg19: chr1-196642233; COSMIC: COSV62776782; COSMIC: COSV62776782;