NM_021023.6:c.803G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP3_ModerateBP6_Very_StrongBS2

The NM_021023.6(CFHR3):c.803G>T(p.Cys268Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,509,440 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000052 ( 15 hom. )

Consequence

CFHR3
NM_021023.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

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: Benign. The variant received -10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

BP6

Variant 1-196793323-G-T is Benign according to our data. Variant chr1-196793323-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 523008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021023.6. 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
	CFHR3	NM_021023.6	MANE Select	c.803G>T	p.Cys268Phe	missense	Exon 6 of 6	NP_066303.2
	CFHR3	NM_001166624.2		c.620G>T	p.Cys207Phe	missense	Exon 5 of 5	NP_001160096.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFHR3	ENST00000367425.9	TSL:1 MANE Select	c.803G>T	p.Cys268Phe	missense	Exon 6 of 6	ENSP00000356395.5
ENSG00000289697	ENST00000696032.1		c.4325G>T	p.Cys1442Phe	missense	Exon 27 of 27	ENSP00000512341.1
CFHR3	ENST00000907755.1		c.794G>T	p.Cys265Phe	missense	Exon 6 of 6	ENSP00000577814.1

Frequencies

GnomAD3 genomes

AF:

0.0000146

AC:

AN:

136698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000255

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000943

AC:

AN:

233198

AF XY:

0.0000953

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000946

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000517

AC:

AN:

1372742

Hom.:

Cov.:

AF XY:

0.0000719

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:

0.0000512

AC:

AN:

39080

South Asian (SAS)

AF:

0.000740

AC:

AN:

75672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50758

Middle Eastern (MID)

AF:

0.000201

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

1052150

Other (OTH)

AF:

0.0000356

AC:

AN:

56130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000146

AC:

AN:

136698

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

66422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32792

American (AMR)

AF:

0.00

AC:

AN:

14106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3186

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.000255

AC:

AN:

3924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64504

Other (OTH)

AF:

0.00

AC:

AN:

1868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

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:

0.00

Hom.:

ExAC

AF:

0.000105

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Age related macular degeneration 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.0078

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

PhyloP100

4.8

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.83

Sift

Uncertain

0.019

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.56

MutPred

0.79

Loss of loop (P = 0.1242)

MVP

0.93

MPC

0.038

ClinPred

0.95

GERP RS

3.6

Varity_R

0.41

gMVP

0.80

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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