NM_000186.4:c.2850G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000186.4(CFH):c.2850G>T(p.Gln950His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,613,902 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q950Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 25 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11

Conservation

PhyloP100: -0.600

Publications

48 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037262112).

BP6

Variant 1-196740686-G-T is Benign according to our data. Variant chr1-196740686-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294510.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00399 (607/152148) while in subpopulation NFE AF = 0.0061 (415/68018). AF 95% confidence interval is 0.00562. There are 0 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 25 AD,AR,Unknown,SD 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.2850G>T	p.Gln950His	missense	Exon 18 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.2850G>T	p.Gln950His	missense	Exon 18 of 22	ENSP00000356399.4	P08603
ENSG00000289697	ENST00000696032.1		c.2850G>T	p.Gln950His	missense	Exon 18 of 27	ENSP00000512341.1	A0A8Q3SIA1
CFH	ENST00000466229.5	TSL:1	n.4866G>T		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes

AF:

0.00399

AC:

607

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00394

AC:

990

AN:

251400

AF XY:

0.00383

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00598

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00469

AC:

6862

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

3342

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33472

American (AMR)

AF:

0.00215

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

437

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00167

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00527

AC:

5857

AN:

1111948

Other (OTH)

AF:

0.00532

AC:

321

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

354

709

1063

1418

1772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<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:

0.00399

AC:

607

AN:

152148

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

274

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41500

American (AMR)

AF:

0.00386

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00610

AC:

415

AN:

68018

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00536

Hom.:

Bravo

AF:

0.00422

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00358

AC:

435

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00433

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Age related macular degeneration 4 (1)

Atypical hemolytic-uremic syndrome (1)

Basal laminar drusen (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)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.50

M_CAP

Benign

0.061

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.93

PhyloP100

-0.60

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.019

Vest4

0.90

MutPred

0.80

Gain of disorder (P = 0.1052)

MVP

0.95

MPC

0.58

ClinPred

0.031

GERP RS

-4.9

gMVP

0.69

Mutation Taster

=44/42

polymorphism

(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

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