rs2274700

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -17 ACMG points: 0P and 17B. BA1BP4_StrongBP6_StrongBP7

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 cumulative frequency of 0.422 (AC=679,796) in the gnomAD database across 1,610,552 control chromosomes, including 145,615 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.541. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant position is a cancer hotspot (cancerhotspots.org) with 2 samples affected at this amino acid position.

Frequency

Genomes: 𝑓 0.44 ( 14793 hom., cov: 31)

Exomes 𝑓: 0.42 ( 130822 hom. )

Consequence

CFH
NM_000186.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.485

Publications

116 publications found

Variant links:

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
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

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000186.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5410 — exceeds 5%% threshold (BA1 applied)

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.1419G>A	p.Ala473Ala	synonymous	Exon 10 of 22	NP_000177.2

Ensembl Transcripts

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	P08603
ENSG00000289697	ENST00000696032.1		c.1419G>A	p.Ala473Ala	synonymous	Exon 10 of 27	ENSP00000512341.1	A0A8Q3SIA1
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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.424

AC XY:

308017

AN XY:

725824

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17594

35188

52781

70375

87969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14050

28100

42150

56200

70250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.439

AC:

66678

AN:

151756

Hom.:

14793

Cov.:

AF XY:

0.446

AC XY:

33037

AN XY:

74146

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1941

3882

5824

7765

9706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.441

AC:

54031

AN:

122594

Turkish Variome

AF:

0.468

AC:

3145

AN:

6718

Hom.:

751

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.410

AC:

3674

AN:

8960

Hom.:

763

ABraOM SABE-WGS-1171

AF:

0.471

AC:

1103

AN:

2342

Hom.:

263

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Age related macular degeneration 4 (2)

Basal laminar drusen (2)

Hemolytic uremic syndrome, atypical, susceptibility to, 1 (2)

not specified (2)

Atypical hemolytic-uremic syndrome (1)

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)

Factor H deficiency (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

(source)

DANN

Benign

0.15

PhyloP100

0.48

Mutation Taster

=84/16

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over