Genetic Variant CFHR3:p.Phe34ArgfsTer10 (chr1-196779200-CTATTTCA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021023.6(CFHR3):c.99_105delATTTCAT(p.Phe34ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 1,530,002 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000044 ( 1 hom., cov: 25)

Exomes 𝑓: 0.00010 ( 28 hom. )

Consequence

CFHR3
NM_021023.6 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90

Publications

0 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_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 28 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR3	NM_021023.6	MANE Select	c.99_105delATTTCAT	p.Phe34ArgfsTer10	frameshift	Exon 2 of 6	NP_066303.2	Q02985-1
	CFHR3	NM_001166624.2		c.99_105delATTTCAT	p.Phe34ArgfsTer10	frameshift	Exon 2 of 5	NP_001160096.1	Q02985-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFHR3	ENST00000367425.9	TSL:1 MANE Select	c.99_105delATTTCAT	p.Phe34ArgfsTer10	frameshift	Exon 2 of 6	ENSP00000356395.5	Q02985-1
ENSG00000289697	ENST00000696032.1		c.3621_3627delATTTCAT	p.Phe1208ArgfsTer10	frameshift	Exon 23 of 27	ENSP00000512341.1	A0A8Q3SIA1
CFHR3	ENST00000471440.6	TSL:1	c.99_105delATTTCAT	p.Phe34ArgfsTer10	frameshift	Exon 2 of 5	ENSP00000436258.1	Q6NSD3

Frequencies

GnomAD3 genomes

AF:

0.0000438

AC:

AN:

136962

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000929

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000252

AC:

AN:

238034

AF XY:

0.0000312

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:

0.0000554

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

143

AN:

1393040

Hom.:

AF XY:

0.0000925

AC XY:

AN XY:

691796

show subpopulations

African (AFR)

AF:

0.0000361

AC:

AN:

27710

American (AMR)

AF:

0.00

AC:

AN:

43986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24348

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00

AC:

AN:

76614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5090

European-Non Finnish (NFE)

AF:

0.000129

AC:

137

AN:

1066048

Other (OTH)

AF:

0.0000873

AC:

AN:

57282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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:

0.0000438

AC:

AN:

136962

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

66564

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32802

American (AMR)

AF:

0.00

AC:

AN:

14232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3186

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

3950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000929

AC:

AN:

64578

Other (OTH)

AF:

0.00

AC:

AN:

1834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000169

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Age related macular degeneration 1;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=187/13

disease causing (fs/PTC)

(source)

Splicing

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