Genetic Variant NM_021023.6:c.209T>C (chr1-196779312-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021023.6(CFHR3):c.209T>C(p.Ile70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000817 in 1,529,400 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000037 ( 2 hom., cov: 25)

Exomes 𝑓: 0.000086 ( 23 hom. )

Consequence

CFHR3
NM_021023.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1973246).

BS2

High Homozygotes in GnomAd4 at 2 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.209T>C	p.Ile70Thr	missense	Exon 2 of 6	NP_066303.2	Q02985-1
	CFHR3	NM_001166624.2		c.209T>C	p.Ile70Thr	missense	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.209T>C	p.Ile70Thr	missense	Exon 2 of 6	ENSP00000356395.5	Q02985-1
ENSG00000289697	ENST00000696032.1		c.3731T>C	p.Ile1244Thr	missense	Exon 23 of 27	ENSP00000512341.1	A0A8Q3SIA1
CFHR3	ENST00000471440.6	TSL:1	c.209T>C	p.Ile70Thr	missense	Exon 2 of 5	ENSP00000436258.1	Q6NSD3

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

136622

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:

0.00370

Gnomad NFE

AF:

0.0000310

Gnomad OTH

AF:

0.00110

GnomAD2 exomes

AF:

0.0000629

AC:

AN:

238384

AF XY:

0.0000700

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:

0.0000828

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000862

AC:

120

AN:

1392656

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

691658

show subpopulations

African (AFR)

AF:

0.0000361

AC:

AN:

27714

American (AMR)

AF:

0.00

AC:

AN:

43994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24358

East Asian (EAS)

AF:

0.00

AC:

AN:

39490

South Asian (SAS)

AF:

0.0000913

AC:

AN:

76634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52486

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5110

European-Non Finnish (NFE)

AF:

0.0000920

AC:

AN:

1065574

Other (OTH)

AF:

0.000105

AC:

AN:

57296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000366

AC:

AN:

136744

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

66584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32712

American (AMR)

AF:

0.00

AC:

AN:

14124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3184

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

3942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10112

Middle Eastern (MID)

AF:

0.00394

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000310

AC:

AN:

64562

Other (OTH)

AF:

0.00108

AC:

AN:

1844

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

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000862

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.092

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.041

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.3

PhyloP100

3.3

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.20

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.22

MVP

0.70

MPC

0.53

ClinPred

0.31

GERP RS

2.9

Varity_R

0.27

gMVP

0.73

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over