Variant 1-196905199-T-A 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.348T>A(p.Asn116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,611,112 control chromosomes in the GnomAD database, including 81 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 39 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 42 hom. )

Consequence

CFHR4
NM_001201550.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.765

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=0.015306085).

BP6

Variant 1-196905199-T-A is Benign according to our data. Variant chr1-196905199-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1336294.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 = 0.00678 (1028/151672) while in subpopulation AFR AF= 0.0239 (985/41196). AF 95% confidence interval is 0.0227. There are 39 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR4	NM_001201550.3 linkuse as main transcript	c.348T>A	p.Asn116Lys	missense_variant	3/10	ENST00000608469.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR4	ENST00000608469.6 linkuse as main transcript	c.348T>A	p.Asn116Lys	missense_variant	3/10	1	NM_001201550.3	P4	Q92496-1

Frequencies

GnomAD3 genomes

AF:

0.00676

AC:

1024

AN:

151556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00178

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000948

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00161

AC:

398

AN:

246796

Hom.:

AF XY:

0.00123

AC XY:

164

AN XY:

133862

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.000786

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000989

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000673

AC:

982

AN:

1459440

Hom.:

Cov.:

AF XY:

0.000568

AC XY:

412

AN XY:

725980

show subpopulations

Gnomad4 AFR exome

AF:

0.0248

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.00678

AC:

1028

AN:

151672

Hom.:

Cov.:

AF XY:

0.00670

AC XY:

497

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.0239

Gnomad4 AMR

AF:

0.00178

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000948

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00359

Hom.:

Bravo

AF:

0.00739

ExAC

AF:

0.00210

AC:

255

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

0.074

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.018

DANN

Benign

0.55

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.12

T;T

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.0

.;N

MutationTaster

Benign

1.0

N;N;N;N

PROVEAN

Benign

0.61

N;.

REVEL

Benign

0.10

Sift

Benign

0.15

T;.

Sift4G

Benign

0.73

T;.

Vest4

0.062

MutPred

0.54

Gain of methylation at N115 (P = 0.0017);.;

MVP

0.10

MPC

0.075

ClinPred

0.030

GERP RS

-4.0

Varity_R

0.050

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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