Variant 1-196774900-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021023.6(CFHR3):c.14T>C(p.Ile5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,528,846 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000095 ( 4 hom., cov: 25)

Exomes 𝑓: 0.000039 ( 8 hom. )

Consequence

CFHR3
NM_021023.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.162

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039183855).

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR3	NM_021023.6 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant	1/6	ENST00000367425.9
CFHR3	NM_001166624.2 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR3	ENST00000367425.9 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant	1/6	1	NM_021023.6	P1	Q02985-1
CFHR3	ENST00000471440.6 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant	1/5	1
CFHR3	ENST00000391985.7 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant	1/5	2			Q02985-2
CFHR3	ENST00000367427.7 linkuse as main transcript	c.14T>C	p.Ile5Thr	missense_variant, NMD_transcript_variant	1/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000948

AC:

AN:

137140

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:

0.00108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000310

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000713

AC:

AN:

238298

Hom.:

AF XY:

0.0000856

AC XY:

AN XY:

128486

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:

0.0000368

Gnomad FIN exome

AF:

0.000519

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000388

AC:

AN:

1391706

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

691172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000117

Gnomad4 FIN exome

AF:

0.000649

Gnomad4 NFE exome

AF:

0.00000563

Gnomad4 OTH exome

AF:

0.0000874

GnomAD4 genome

AF:

0.0000948

AC:

AN:

137140

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

66714

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:

0.00108

Gnomad4 NFE

AF:

0.0000310

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000104

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

Aug 17, 2022

The c.14T>C (p.I5T) alteration is located in exon 1 (coding exon 1) of the CFHR3 gene. This alteration results from a T to C substitution at nucleotide position 14, causing the isoleucine (I) at amino acid position 5 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

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.052

T;T;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.52

T;.;T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.039

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.30

N;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.047

D;D;D;.

Sift4G

Uncertain

0.049

D;D;D;D

Polyphen

0.90

P;B;.;.

Vest4

0.045

MutPred

0.57

Loss of stability (P = 0.001);Loss of stability (P = 0.001);Loss of stability (P = 0.001);Loss of stability (P = 0.001);

MVP

0.15

MPC

0.12

ClinPred

0.025

GERP RS

0.26

Varity_R

0.043

gMVP

0.28

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