rs1061147

Variant names:

• chr1-196685194-A-C
• rs1061147
• NM_000186.4:c.921A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-196685194-A-C
• chr1-196685194-A-G
• chr1-196685194-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000186.4(CFH):​c.921A>C​(p.Ala307Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,612,176 control chromosomes in the GnomAD database, including 328,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30604 hom., cov: 31)
  • Exomes 𝑓: 0.63 (298201 hom.)
• Consequence: CFH NM_000186.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.175
• Publications: 91 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=-0.9).
• BP6: Variant 1-196685194-A-C is Benign according to our data. Variant chr1-196685194-A-C is described in ClinVar as Benign. ClinVar VariationId is 294488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.175 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 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.921A>C	p.Ala307Ala	synonymous	Exon 7 of 22	NP_000177.2
	CFH	NM_001014975.3		c.921A>C	p.Ala307Ala	synonymous	Exon 7 of 10	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.921A>C	p.Ala307Ala	synonymous	Exon 7 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.921A>C	p.Ala307Ala	synonymous	Exon 7 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.921A>C	p.Ala307Ala	synonymous	Exon 7 of 10	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95518 AN: 151684 Hom.: 30581 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.676 AC: 169659 AN: 250890 AF XY: 0.671

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.954

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.635 AC: 927090 AN: 1460374 Hom.: 298201 Cov.: 48 AF XY: 0.636 AC XY: 461970 AN XY: 726556

African (AFR) AF: 0.578 AC: 19307 AN: 33416

American (AMR) AF: 0.821 AC: 36630 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17056 AN: 26098

East Asian (EAS) AF: 0.940 AC: 37277 AN: 39658

South Asian (SAS) AF: 0.694 AC: 59860 AN: 86234

European-Finnish (FIN) AF: 0.559 AC: 29873 AN: 53414

Middle Eastern (MID) AF: 0.630 AC: 3631 AN: 5760

European-Non Finnish (NFE) AF: 0.616 AC: 684814 AN: 1110834

Other (OTH) AF: 0.641 AC: 38642 AN: 60326

GnomAD4 genome AF: 0.630 AC: 95581 AN: 151802 Hom.: 30604 Cov.: 31 AF XY: 0.633 AC XY: 46991 AN XY: 74192

African (AFR) AF: 0.578 AC: 23939 AN: 41396

American (AMR) AF: 0.730 AC: 11090 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2296 AN: 3468

East Asian (EAS) AF: 0.948 AC: 4875 AN: 5144

South Asian (SAS) AF: 0.720 AC: 3475 AN: 4824

European-Finnish (FIN) AF: 0.562 AC: 5932 AN: 10564

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

European-Non Finnish (NFE) AF: 0.618 AC: 41931 AN: 67900

Other (OTH) AF: 0.656 AC: 1378 AN: 2102

Alfa AF: 0.618 Hom.: 97823

Bravo AF: 0.643

Asia WGS AF: 0.778 AC: 2704 AN: 3476

EpiCase AF: 0.632

EpiControl AF: 0.628

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.90
CADD	Benign	3.9
DANN	Benign	0.43
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs1061147; hg19: chr1-196654324; COSMIC: COSV62778986;