rs460897

Variant names:

• chr1-196747189-C-T
• rs460897
• NM_000186.4:c.3572C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_000186.4(CFH):​c.3572C>T​(p.Ser1191Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1191W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 0.406
• Publications: 57 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):

• C3 glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• basal laminar drusen

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000186.4
• PP5: Variant 1-196747189-C-T is Pathogenic according to our data. Variant chr1-196747189-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3572C>T	p.Ser1191Leu	missense	Exon 22 of 22	NP_000177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.3572C>T	p.Ser1191Leu	missense	Exon 22 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.3572C>T	p.Ser1191Leu	missense	Exon 22 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.6670C>T		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Atypical hemolytic-uremic syndrome (1)
1	-	-	CFH-related disorder (1)
1	-	-	Factor H deficiency (1)
1	-	-	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)
1	-	-	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
PhyloP100		0.41
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.26
Sift	Uncertain	0.026	D
Sift4G	Benign	0.086	T
Vest4		0.35
MutPred		0.84		Loss of disorder (P = 0.0253)
MVP		0.99
MPC		1.3
ClinPred		0.37	T
GERP RS		-1.0
gMVP		0.98
Mutation Taster		=12/87	disease causing (ClinVar)

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: rs460897; hg19: chr1-196716319; COSMIC: COSV66410930;