Variant 1-196905129-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_001201550.3(CFHR4):c.278T>C(p.Val93Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,601,886 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V93I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 9 hom. )

Consequence

CFHR4
NM_001201550.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.871

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:

CFHR4 (HGNC:):

CFHR4 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=0.006133765).

BS2

High Homozygotes in GnomAd4 at 15 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR4	NM_001201550.3 linkuse as main transcript	c.278T>C	p.Val93Ala	missense_variant	3/10	ENST00000608469.6	NP_001188479.1	Q92496-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR4	ENST00000608469.6 linkuse as main transcript	c.278T>C	p.Val93Ala	missense_variant	3/10	1	NM_001201550.3	ENSP00000477162.2		Q92496-1

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

323

AN:

151704

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00741

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

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:

0.000132

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000546

AC:

131

AN:

239950

Hom.:

AF XY:

0.000445

AC XY:

AN XY:

130336

show subpopulations

Gnomad AFR exome

AF:

0.00725

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000738

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000220

AC:

319

AN:

1450066

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

133

AN XY:

721112

show subpopulations

Gnomad4 AFR exome

AF:

0.00707

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000715

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000461

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.00213

AC:

323

AN:

151820

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

167

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00738

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00243

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000578

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 12, 2024

BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.060

Sift

Benign

0.043

D;.

Sift4G

Uncertain

0.0060

D;.

Vest4

0.063

MVP

0.030

MPC

0.15

ClinPred

0.0054

GERP RS

2.3

Varity_R

0.043

gMVP

0.56

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