1-196713817-G-A

Variant names:

• chr1-196713817-G-A
• rs2274700
• NM_000186.4:c.1419G>A

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.1419G>A​(p.Ala473Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,610,552 control chromosomes in the GnomAD database, including 145,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A473A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.44 (14793 hom., cov: 31)
  • Exomes 𝑓: 0.42 (130822 hom.)
• Consequence: CFH NM_000186.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.485
• Publications: 116 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-196713817-G-A is Benign according to our data. Variant chr1-196713817-G-A is described in ClinVar as Benign. ClinVar VariationId is 294491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.485 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 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.1419G>A	p.Ala473Ala	synonymous	Exon 10 of 22	NP_000177.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1419G>A	p.Ala473Ala	synonymous	Exon 10 of 22	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.1419G>A	p.Ala473Ala	synonymous	Exon 10 of 27	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.3435G>A		non_coding_transcript_exon	Exon 5 of 16

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66624 AN: 151640 Hom.: 14776 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.470

GnomAD2 exomes AF: 0.444 AC: 111026 AN: 250332 AF XY: 0.448

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.420 AC: 613118 AN: 1458796 Hom.: 130822 Cov.: 32 AF XY: 0.424 AC XY: 308017 AN XY: 725824

African (AFR) AF: 0.471 AC: 15728 AN: 33362

American (AMR) AF: 0.466 AC: 20748 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13276 AN: 26074

East Asian (EAS) AF: 0.442 AC: 17490 AN: 39534

South Asian (SAS) AF: 0.545 AC: 46959 AN: 86190

European-Finnish (FIN) AF: 0.397 AC: 21189 AN: 53370

Middle Eastern (MID) AF: 0.464 AC: 2667 AN: 5746

European-Non Finnish (NFE) AF: 0.405 AC: 449343 AN: 1109734

Other (OTH) AF: 0.427 AC: 25718 AN: 60236

GnomAD4 genome AF: 0.439 AC: 66678 AN: 151756 Hom.: 14793 Cov.: 31 AF XY: 0.446 AC XY: 33037 AN XY: 74146

African (AFR) AF: 0.465 AC: 19241 AN: 41392

American (AMR) AF: 0.485 AC: 7384 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1811 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2283 AN: 5144

South Asian (SAS) AF: 0.559 AC: 2690 AN: 4816

European-Finnish (FIN) AF: 0.401 AC: 4215 AN: 10510

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27693 AN: 67890

Other (OTH) AF: 0.472 AC: 995 AN: 2108

Alfa AF: 0.388 Hom.: 13086

Bravo AF: 0.442

Asia WGS AF: 0.525 AC: 1823 AN: 3474

EpiCase AF: 0.426

EpiControl AF: 0.419

ClinVar

ClinVar submissions as Germline

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	3.7
DANN	Benign	0.15
PhyloP100		0.48
Mutation Taster		=84/16	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: rs2274700; hg19: chr1-196682947; COSMIC: COSV66406791;