1-196690107-C-T

Variant names:

• chr1-196690107-C-T
• rs1061170
• NM_000186.4:c.1204C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000186.4(CFH):​c.1204C>T​(p.His402Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,610,204 control chromosomes in the GnomAD database, including 330,962 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H402D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (31992 hom., cov: 31)
  • Exomes 𝑓: 0.64 (298970 hom.)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -8.33
• Publications: 834 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.2569295E-6).
• BP6: Variant 1-196690107-C-T is Benign according to our data. Variant chr1-196690107-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294490.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.1204C>T	p.His402Tyr	missense	Exon 9 of 22	NP_000177.2
	CFH	NM_001014975.3		c.1204C>T	p.His402Tyr	missense	Exon 9 of 10	NP_001014975.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1204C>T	p.His402Tyr	missense	Exon 9 of 22	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.1204C>T	p.His402Tyr	missense	Exon 9 of 27	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.1204C>T	p.His402Tyr	missense	Exon 9 of 10	ENSP00000487250.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97836 AN: 151784 Hom.: 31967 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.663

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.665

GnomAD2 exomes AF: 0.680 AC: 169954 AN: 250026 AF XY: 0.673

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.954

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.636 AC: 927619 AN: 1458302 Hom.: 298970 Cov.: 50 AF XY: 0.637 AC XY: 462112 AN XY: 725588

African (AFR) AF: 0.630 AC: 21019 AN: 33378

American (AMR) AF: 0.824 AC: 36705 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17060 AN: 26100

East Asian (EAS) AF: 0.940 AC: 37228 AN: 39602

South Asian (SAS) AF: 0.694 AC: 59819 AN: 86170

European-Finnish (FIN) AF: 0.559 AC: 29829 AN: 53332

Middle Eastern (MID) AF: 0.631 AC: 3633 AN: 5758

European-Non Finnish (NFE) AF: 0.616 AC: 683562 AN: 1109172

Other (OTH) AF: 0.644 AC: 38764 AN: 60228

GnomAD4 genome AF: 0.645 AC: 97903 AN: 151902 Hom.: 31992 Cov.: 31 AF XY: 0.647 AC XY: 48054 AN XY: 74232

African (AFR) AF: 0.629 AC: 26039 AN: 41408

American (AMR) AF: 0.738 AC: 11238 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2295 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4874 AN: 5138

South Asian (SAS) AF: 0.720 AC: 3470 AN: 4820

European-Finnish (FIN) AF: 0.563 AC: 5946 AN: 10568

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.618 AC: 41974 AN: 67948

Other (OTH) AF: 0.664 AC: 1404 AN: 2114

Alfa AF: 0.640 Hom.: 26141

Bravo AF: 0.660

TwinsUK AF: 0.612 AC: 2270

ALSPAC AF: 0.622 AC: 2398

ESP6500AA AF: 0.637 AC: 2808

ESP6500EA AF: 0.618 AC: 5312

ExAC AF: 0.671 AC: 81367

Asia WGS AF: 0.781 AC: 2716 AN: 3478

EpiCase AF: 0.632

EpiControl AF: 0.628

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Age related macular degeneration 4 (2)
-	-	2	Basal laminar drusen (2)
-	-	2	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0010
DANN	Benign	0.22
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.00085	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000043	T
MetaSVM	Benign	-1.0	T
PhyloP100		-8.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.087
MPC		0.16
ClinPred		0.023	T
GERP RS		-9.1
gMVP		0.58
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1061170; hg19: chr1-196659237; COSMIC: COSV62776341;