Variant chr1-196779312-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR3	NM_021023.6 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant	2/6	ENST00000367425.9
CFHR3	NM_001166624.2 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR3	ENST00000367425.9 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant	2/6	1	NM_021023.6	P1	Q02985-1
CFHR3	ENST00000471440.6 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant	2/5	1
CFHR3	ENST00000391985.7 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant	2/5	2			Q02985-2
CFHR3	ENST00000367427.7 linkuse as main transcript	c.209T>C	p.Ile70Thr	missense_variant, NMD_transcript_variant	2/7	5

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

GnomAD3 exomes

AF:

0.0000629

AC:

AN:

238384

Hom.:

AF XY:

0.0000700

AC XY:

AN XY:

128542

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 SAS exome

AF:

0.000184

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

Gnomad4 AFR exome

AF:

0.0000361

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000913

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000920

Gnomad4 OTH exome

AF:

0.000105

GnomAD4 genome

AF:

0.0000366

AC:

AN:

136744

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

66584

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000310

Gnomad4 OTH

AF:

0.00108

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.209T>C (p.I70T) alteration is located in exon 2 (coding exon 2) of the CFHR3 gene. This alteration results from a T to C substitution at nucleotide position 209, causing the isoleucine (I) at amino acid position 70 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.092

LIST_S2

Uncertain

0.87

D;.;T;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.3

M;.;M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.3

D;D;D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.22

MVP

0.70

MPC

0.53

ClinPred

0.31

GERP RS

2.9

Varity_R

0.27

gMVP

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over