dbSNP rs745503234: CFHR3:p.Cys268Tyr (chr1-196793323-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021023.6(CFHR3):c.803G>A(p.Cys268Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,372,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C268F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CFHR3
NM_021023.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

3 publications found

Variant links:

Genes affected

CFHR3 (HGNC:16980): (complement factor H related 3) The protein encoded by this gene is a secreted protein, which belongs to the complement factor H-related protein family. It binds to heparin, and may be involved in complement regulation. Mutations in this gene are associated with decreased risk of age-related macular degeneration, and with an increased risk of atypical hemolytic-uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

CFHR3 Gene-Disease associations (from GenCC):

hemolytic uremic syndrome, atypical, susceptibility to, 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFHR3 links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR3	NM_021023.6 link	c.803G>A	p.Cys268Tyr	missense_variant	Exon 6 of 6	ENST00000367425.9	NP_066303.2	Q02985-1
CFHR3	NM_001166624.2 link	c.620G>A	p.Cys207Tyr	missense_variant	Exon 5 of 5		NP_001160096.1	Q02985-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR3	ENST00000367425.9 link	c.803G>A	p.Cys268Tyr	missense_variant	Exon 6 of 6	1	NM_021023.6	ENSP00000356395.5		Q02985-1
ENSG00000289697	ENST00000696032.1 link	c.4325G>A	p.Cys1442Tyr	missense_variant	Exon 27 of 27			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000429

AC:

AN:

233198

AF XY:

0.00000794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000219

AC:

AN:

1372742

Hom.:

Cov.:

AF XY:

0.00000440

AC XY:

AN XY:

681190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27014

American (AMR)

AF:

0.00

AC:

AN:

43324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23650

East Asian (EAS)

AF:

0.00

AC:

AN:

39080

South Asian (SAS)

AF:

0.0000396

AC:

AN:

75672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1052150

Other (OTH)

AF:

0.00

AC:

AN:

56130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.69

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

4.8

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.061

T;D

Sift4G

Uncertain

0.039

D;D

Polyphen

1.0

D;.

Vest4

0.58

MutPred

0.77

Loss of loop (P = 0.1242);.;

MVP

0.97

MPC

0.037

ClinPred

0.94

GERP RS

3.6

Varity_R

0.26

gMVP

0.85

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over