rs35274867

Positions:

chr1-196743466-A-T

Variant summary

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

The NM_000186.4(CFH):c.3148A>T(p.Asn1050Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,613,744 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. N1050N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 30 hom., cov: 33)

Exomes 𝑓: 0.018 ( 281 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.65

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]

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 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=0.0077705383).

BP6

Variant 1-196743466-A-T is Benign according to our data. Variant chr1-196743466-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 294520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196743466-A-T is described in Lovd as [Benign]. Variant chr1-196743466-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0192 (2928/152318) while in subpopulation AFR AF= 0.0274 (1140/41588). AF 95% confidence interval is 0.0261. There are 30 homozygotes in gnomad4. There are 1364 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4 linkuse as main transcript	c.3148A>T	p.Asn1050Tyr	missense_variant	20/22	ENST00000367429.9	NP_000177.2	P08603A0A024R962

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.3148A>T	p.Asn1050Tyr	missense_variant	20/22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 linkuse as main transcript	c.3148A>T	p.Asn1050Tyr	missense_variant	20/27			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2929

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0200

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0143

AC:

3601

AN:

251412

Hom.:

AF XY:

0.0140

AC XY:

1907

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.00781

Gnomad ASJ exome

AF:

0.00943

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00722

Gnomad FIN exome

AF:

0.00850

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0179

AC:

26099

AN:

1461426

Hom.:

281

Cov.:

AF XY:

0.0173

AC XY:

12592

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0270

Gnomad4 AMR exome

AF:

0.00865

Gnomad4 ASJ exome

AF:

0.00884

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00802

Gnomad4 FIN exome

AF:

0.00872

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0169

GnomAD4 genome

AF:

0.0192

AC:

2928

AN:

152318

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0274

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0200

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.0223

AC:

192

ExAC

AF:

0.0151

AC:

1835

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CFH: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Basal laminar drusen

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Age related macular degeneration 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Factor H deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Atypical hemolytic-uremic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 06, 2021

- -

Thrombotic microangiopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

John Atkinson Laboratory, Washington University School of Medicine in St. Louis

Jun 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.7

DANN

Uncertain

0.98

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.091

Sift

Benign

0.17

Sift4G

Benign

0.24

Vest4

0.11

MPC

0.18

ClinPred

0.0060

GERP RS

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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