chr1-196685194-A-C

Position:

• chr1-196685194-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000186.4(CFH):​c.921A>C​(p.Ala307Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,612,176 control chromosomes in the GnomAD database, including 328,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30604 hom., cov: 31)
  • Exomes 𝑓: 0.63 (298201 hom.)
• Consequence: CFH NM_000186.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.175

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]

ENSG00000289697 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-196685194-A-C is Benign according to our data. Variant chr1-196685194-A-C is described in ClinVar as [Benign]. Clinvar id is 294488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196685194-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.175 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.921A>C	p.Ala307Ala	synonymous_variant	7/22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.921A>C	p.Ala307Ala	synonymous_variant	7/10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.921A>C	p.Ala307Ala	synonymous_variant	7/22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.921A>C	p.Ala307Ala	synonymous_variant	7/27			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95518 AN: 151684 Hom.: 30581 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.656

GnomAD3 exomes AF: 0.676 AC: 169659 AN: 250890 Hom.: 59052 AF XY: 0.671 AC XY: 90943 AN XY: 135566

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.954

Gnomad SAS exome AF: 0.698

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.635 AC: 927090 AN: 1460374 Hom.: 298201 Cov.: 48 AF XY: 0.636 AC XY: 461970 AN XY: 726556

Gnomad4 AFR exome AF: 0.578

Gnomad4 AMR exome AF: 0.821

Gnomad4 ASJ exome AF: 0.654

Gnomad4 EAS exome AF: 0.940

Gnomad4 SAS exome AF: 0.694

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.630 AC: 95581 AN: 151802 Hom.: 30604 Cov.: 31 AF XY: 0.633 AC XY: 46991 AN XY: 74192

Gnomad4 AFR AF: 0.578

Gnomad4 AMR AF: 0.730

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.720

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.656

Alfa AF: 0.604 Hom.: 48080

Bravo AF: 0.643

Asia WGS AF: 0.778 AC: 2704 AN: 3476

EpiCase AF: 0.632

EpiControl AF: 0.628

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 18421087, 15870199) -

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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 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 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Basal laminar drusen Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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 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 submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1061147; hg19: chr1-196654324; COSMIC: COSV62778986;