dbSNP rs425757: CFHR1:p.His157Tyr (chr1-196828108-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002113.3(CFHR1):c.469C>T(p.His157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,053,124 control chromosomes in the GnomAD database, including 122,751 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.31 ( 7247 hom., cov: 16)

Exomes 𝑓: 0.30 ( 115504 hom. )

Consequence

CFHR1
NM_002113.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.31

Variant links:

Genes affected

CFHR1 (HGNC:4888): (complement factor H related 1) This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome. [provided by RefSeq, Oct 2009]

CFHR1 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=0.0069996417).

BP6

Variant 1-196828108-C-T is Benign according to our data. Variant chr1-196828108-C-T is described in ClinVar as [Benign]. Clinvar id is 1179673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196828108-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR1	NM_002113.3 link	c.469C>T	p.His157Tyr	missense_variant	Exon 4 of 6	ENST00000320493.10	NP_002104.2	Q03591

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR1	ENST00000320493.10 link	c.469C>T	p.His157Tyr	missense_variant	Exon 4 of 6	1	NM_002113.3	ENSP00000314299.5		Q03591

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

29803

AN:

95098

Hom.:

7230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.349

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.381

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.260

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.298

AC:

49225

AN:

164932

Hom.:

20239

AF XY:

0.290

AC XY:

25786

AN XY:

88956

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.385

Gnomad ASJ exome

AF:

0.387

Gnomad EAS exome

AF:

0.443

Gnomad SAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.298

AC:

285137

AN:

957956

Hom.:

115504

Cov.:

AF XY:

0.300

AC XY:

143514

AN XY:

479072

show subpopulations

Gnomad4 AFR exome

AF:

0.434

Gnomad4 AMR exome

AF:

0.396

Gnomad4 ASJ exome

AF:

0.391

Gnomad4 EAS exome

AF:

0.474

Gnomad4 SAS exome

AF:

0.319

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.280

Gnomad4 OTH exome

AF:

0.319

GnomAD4 genome

AF:

0.313

AC:

29835

AN:

95168

Hom.:

7247

Cov.:

AF XY:

0.308

AC XY:

14051

AN XY:

45608

show subpopulations

Gnomad4 AFR

AF:

0.349

Gnomad4 AMR

AF:

0.382

Gnomad4 ASJ

AF:

0.370

Gnomad4 EAS

AF:

0.465

Gnomad4 SAS

AF:

0.245

Gnomad4 FIN

AF:

0.249

Gnomad4 NFE

AF:

0.290

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.438

Hom.:

2195

ESP6500AA

AF:

0.444

AC:

1612

ESP6500EA

AF:

0.245

AC:

2010

ExAC

AF:

0.328

AC:

36989

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.039

DANN

Benign

0.70

DEOGEN2

Benign

0.0019

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

PROVEAN

Benign

-0.39

REVEL

Benign

0.036

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.14

Vest4

0.041

MPC

1.0

ClinPred

0.0066

GERP RS

-4.3

Varity_R

0.039

gMVP

0.38

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