Variant 1-196902544-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001201550.3(CFHR4):c.185C>T(p.Thr62Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,612,252 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 6 hom. )

Consequence

CFHR4
NM_001201550.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.51

Variant links:

Genes affected

CFHR4 (HGNC:16979): (complement factor H related 4) This gene is a member of the complement factor H (CFH) gene family, and encodes one of the 5 CFH-related (CFHR) proteins. These 5 genes are closely linked to the CFH gene on chromosome 1q31-q32. The CFHRs are secreted plasma proteins synthesized primarily by the hepatocytes, and composed of highly-related short consensus repeats (SCRs). This protein enhances the cofactor activity of CFH, and is involved in complement regulation. It can associate with lipoproteins and may play a role in lipid metabolism. Alternatively spliced transcript variants encoding different isoforms (varying in the number of SCRs) have been described for this gene. [provided by RefSeq, Jan 2011]

CFHR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09971753).

BP6

Variant 1-196902544-C-T is Benign according to our data. Variant chr1-196902544-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 806298.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr1-196902544-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR4	NM_001201550.3 linkuse as main transcript	c.185C>T	p.Thr62Ile	missense_variant	2/10	ENST00000608469.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR4	ENST00000608469.6 linkuse as main transcript	c.185C>T	p.Thr62Ile	missense_variant	2/10	1	NM_001201550.3	P4	Q92496-1

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

151362

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000288

AC:

AN:

250090

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000281

AC:

411

AN:

1460778

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

213

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000311

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000191

AC:

AN:

151474

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74002

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000546

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.185C>T (p.T62I) alteration is located in exon 2 (coding exon 2) of the CFHR4 gene. This alteration results from a C to T substitution at nucleotide position 185, causing the threonine (T) at amino acid position 62 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.72

MutationTaster

Benign

1.0

N;N;N;N

PROVEAN

Benign

-1.9

N;.;D

REVEL

Benign

0.24

Sift

Uncertain

0.010

D;.;D

Sift4G

Uncertain

0.032

D;.;D

Polyphen

1.0

.;D;.

Vest4

0.46

MVP

0.37

MPC

0.42

ClinPred

0.39

GERP RS

1.7

Varity_R

0.061

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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