NM_000186.4:c.2016A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000186.4(CFH):c.2016A>G(p.Gln672Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,608,810 control chromosomes in the GnomAD database, including 28,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2399 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26311 hom. )

Consequence

CFH
NM_000186.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.0700

Publications

94 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
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

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 1-196726612-A-G is Benign according to our data. Variant chr1-196726612-A-G is described in ClinVar as Benign. ClinVar VariationId is 294498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 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.2016A>G	p.Gln672Gln	synonymous	Exon 13 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.2016A>G	p.Gln672Gln	synonymous	Exon 13 of 22	ENSP00000356399.4	P08603
ENSG00000289697	ENST00000696032.1		c.2016A>G	p.Gln672Gln	synonymous	Exon 13 of 27	ENSP00000512341.1	A0A8Q3SIA1
CFH	ENST00000466229.5	TSL:1	n.4032A>G		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23159

AN:

152090

Hom.:

2399

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.483

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.204

AC:

51150

AN:

250754

AF XY:

0.196

show subpopulations

Gnomad AFR exome

AF:

0.0573

Gnomad AMR exome

AF:

0.355

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.177

AC:

257139

AN:

1456602

Hom.:

26311

Cov.:

AF XY:

0.175

AC XY:

126598

AN XY:

724974

show subpopulations

African (AFR)

AF:

0.0505

AC:

1686

AN:

33418

American (AMR)

AF:

0.335

AC:

14993

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3161

AN:

26094

East Asian (EAS)

AF:

0.480

AC:

18998

AN:

39552

South Asian (SAS)

AF:

0.142

AC:

12193

AN:

86162

European-Finnish (FIN)

AF:

0.140

AC:

7490

AN:

53406

Middle Eastern (MID)

AF:

0.146

AC:

838

AN:

5752

European-Non Finnish (NFE)

AF:

0.169

AC:

187305

AN:

1107294

Other (OTH)

AF:

0.174

AC:

10475

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

9806

19611

29417

39222

49028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6758

13516

20274

27032

33790

<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:

0.152

AC:

23152

AN:

152208

Hom.:

2399

Cov.:

AF XY:

0.153

AC XY:

11375

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0597

AC:

2480

AN:

41566

American (AMR)

AF:

0.224

AC:

3419

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

405

AN:

3468

East Asian (EAS)

AF:

0.484

AC:

2493

AN:

5156

South Asian (SAS)

AF:

0.150

AC:

725

AN:

4830

European-Finnish (FIN)

AF:

0.143

AC:

1520

AN:

10600

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.169

AC:

11487

AN:

68006

Other (OTH)

AF:

0.156

AC:

329

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

951

1902

2853

3804

4755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.171

Hom.:

4926

Bravo

AF:

0.160

Asia WGS

AF:

0.235

AC:

817

AN:

3476

EpiCase

AF:

0.170

EpiControl

AF:

0.173

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Age related macular degeneration 4 (2)

Basal laminar drusen (2)

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

not provided (2)

not specified (2)

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)

Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.4

(source)

DANN

Benign

0.43

PhyloP100

0.070

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over