Variant 1-196902421-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001201550.3(CFHR4):c.62T>C(p.Val21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,601,254 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 42 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 33 hom. )

Consequence

CFHR4
NM_001201550.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.640

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059503317).

BP6

Variant 1-196902421-T-C is Benign according to our data. Variant chr1-196902421-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1336292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1032/151632) while in subpopulation AFR AF= 0.024 (989/41172). AF 95% confidence interval is 0.0228. There are 42 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR4	NM_001201550.3 linkuse as main transcript	c.62T>C	p.Val21Ala	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.62T>C	p.Val21Ala	missense_variant	2/10	1	NM_001201550.3	P4	Q92496-1

Frequencies

GnomAD3 genomes

AF:

0.00678

AC:

1028

AN:

151524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00529

GnomAD3 exomes

AF:

0.00160

AC:

393

AN:

245264

Hom.:

AF XY:

0.00120

AC XY:

160

AN XY:

132970

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.000771

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000103

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000672

GnomAD4 exome

AF:

0.000655

AC:

949

AN:

1449622

Hom.:

Cov.:

AF XY:

0.000561

AC XY:

405

AN XY:

721338

show subpopulations

Gnomad4 AFR exome

AF:

0.0244

Gnomad4 AMR exome

AF:

0.00100

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000355

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.00681

AC:

1032

AN:

151632

Hom.:

Cov.:

AF XY:

0.00668

AC XY:

495

AN XY:

74102

show subpopulations

Gnomad4 AFR

AF:

0.0240

Gnomad4 AMR

AF:

0.00184

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00524

Alfa

AF:

0.000744

Hom.:

Bravo

AF:

0.00741

ESP6500AA

AF:

0.0242

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00203

AC:

245

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 14, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.028

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.19

T;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;N;N

PROVEAN

Benign

-0.18

N;.;N;.

REVEL

Benign

0.038

Sift

Benign

1.0

T;.;T;.

Sift4G

Uncertain

0.021

D;.;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.15

MVP

0.014

MPC

0.33

ClinPred

0.0053

GERP RS

0.94

Varity_R

0.018

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -3

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