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rs2274700

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000186.4(CFH):c.1419G>A(p.Ala473=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,610,552 control chromosomes in the GnomAD database, including 145,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A473A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 14793 hom., cov: 31)
Exomes 𝑓: 0.42 ( 130822 hom. )

Consequence

CFH
NM_000186.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.485
Variant links:
Genes affected
CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 1-196713817-G-A is Benign according to our data. Variant chr1-196713817-G-A is described in ClinVar as [Benign]. Clinvar id is 294491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196713817-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.485 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFHNM_000186.4 linkuse as main transcriptc.1419G>A p.Ala473= synonymous_variant 10/22 ENST00000367429.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFHENST00000367429.9 linkuse as main transcriptc.1419G>A p.Ala473= synonymous_variant 10/221 NM_000186.4 P2

Frequencies

GnomAD3 genomes
AF:
0.439
AC:
66624
AN:
151640
Hom.:
14776
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.465
Gnomad AMI
AF:
0.258
Gnomad AMR
AF:
0.485
Gnomad ASJ
AF:
0.522
Gnomad EAS
AF:
0.444
Gnomad SAS
AF:
0.558
Gnomad FIN
AF:
0.401
Gnomad MID
AF:
0.456
Gnomad NFE
AF:
0.408
Gnomad OTH
AF:
0.470
GnomAD3 exomes
AF:
0.444
AC:
111026
AN:
250332
Hom.:
25005
AF XY:
0.448
AC XY:
60592
AN XY:
135286
show subpopulations
Gnomad AFR exome
AF:
0.462
Gnomad AMR exome
AF:
0.459
Gnomad ASJ exome
AF:
0.521
Gnomad EAS exome
AF:
0.431
Gnomad SAS exome
AF:
0.546
Gnomad FIN exome
AF:
0.403
Gnomad NFE exome
AF:
0.412
Gnomad OTH exome
AF:
0.430
GnomAD4 exome
AF:
0.420
AC:
613118
AN:
1458796
Hom.:
130822
Cov.:
32
AF XY:
0.424
AC XY:
308017
AN XY:
725824
show subpopulations
Gnomad4 AFR exome
AF:
0.471
Gnomad4 AMR exome
AF:
0.466
Gnomad4 ASJ exome
AF:
0.509
Gnomad4 EAS exome
AF:
0.442
Gnomad4 SAS exome
AF:
0.545
Gnomad4 FIN exome
AF:
0.397
Gnomad4 NFE exome
AF:
0.405
Gnomad4 OTH exome
AF:
0.427
GnomAD4 genome
AF:
0.439
AC:
66678
AN:
151756
Hom.:
14793
Cov.:
31
AF XY:
0.446
AC XY:
33037
AN XY:
74146
show subpopulations
Gnomad4 AFR
AF:
0.465
Gnomad4 AMR
AF:
0.485
Gnomad4 ASJ
AF:
0.522
Gnomad4 EAS
AF:
0.444
Gnomad4 SAS
AF:
0.559
Gnomad4 FIN
AF:
0.401
Gnomad4 NFE
AF:
0.408
Gnomad4 OTH
AF:
0.472
Alfa
AF:
0.382
Hom.:
11061
Bravo
AF:
0.442
Asia WGS
AF:
0.525
AC:
1823
AN:
3474
EpiCase
AF:
0.426
EpiControl
AF:
0.419

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021This variant is associated with the following publications: (PMID: 25087612, 21868097, 22848687, 16299065) -
Basal laminar drusen Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Age related macular degeneration 4 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Factor H deficiency Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Atypical hemolytic-uremic syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 05, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
Cadd
Benign
3.7
Dann
Benign
0.15

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.

Other links and lift over

dbSNP: rs2274700; hg19: chr1-196682947; COSMIC: COSV66406791; API