rs35292876

Variant names:

• chr1-196737512-C-T
• rs35292876
• NM_000186.4:c.2634C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-196737512-C-T
• chr1-196737512-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000186.4(CFH):​c.2634C>T​(p.His878His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,612,918 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (118 hom.)
• Consequence: CFH NM_000186.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.578
• Publications: 27 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-196737512-C-T is Benign according to our data. Variant chr1-196737512-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.578 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00867 (1319/152192) while in subpopulation SAS AF = 0.0222 (107/4820). AF 95% confidence interval is 0.0188. There are 8 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD,SD,Unknown gene

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.2634C>T	p.His878His	synonymous	Exon 17 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.2634C>T	p.His878His	synonymous	Exon 17 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.2634C>T	p.His878His	synonymous	Exon 17 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.4650C>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1316 AN: 152074 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00756

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00984

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0104 AC: 2602 AN: 250892 AF XY: 0.0119

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.00608

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00882

GnomAD4 exome AF: 0.00986 AC: 14399 AN: 1460726 Hom.: 118 Cov.: 31 AF XY: 0.0108 AC XY: 7822 AN XY: 726684

African (AFR) AF: 0.00499 AC: 167 AN: 33438

American (AMR) AF: 0.00644 AC: 288 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 121 AN: 26102

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39546

South Asian (SAS) AF: 0.0295 AC: 2540 AN: 86182

European-Finnish (FIN) AF: 0.00687 AC: 367 AN: 53388

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5762

European-Non Finnish (NFE) AF: 0.00920 AC: 10221 AN: 1111290

Other (OTH) AF: 0.00941 AC: 568 AN: 60330

GnomAD4 genome AF: 0.00867 AC: 1319 AN: 152192 Hom.: 8 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74404

African (AFR) AF: 0.00633 AC: 263 AN: 41536

American (AMR) AF: 0.0102 AC: 156 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4820

European-Finnish (FIN) AF: 0.00756 AC: 80 AN: 10588

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00984 AC: 669 AN: 68004

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0109 Hom.: 29

Bravo AF: 0.00800

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.6
DANN	Benign	0.41
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35292876; hg19: chr1-196706642; COSMIC: COSV66405515;