chr1-196713817-G-A

Position:

• chr1-196713817-G-A

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.1419G>A​(p.Ala473Ala) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.485

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 1-196713817-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	Protein	UniProt
CFH	NM_000186.4	c.1419G>A	p.Ala473Ala	synonymous_variant	10/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1419G>A	p.Ala473Ala	synonymous_variant	10/22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1419G>A	p.Ala473Ala	synonymous_variant	10/27			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66624 AN: 151640 Hom.: 14776 Cov.: 31

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

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

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

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: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: 25087612, 21868097, 22848687, 16299065) -

Hemolytic uremic syndrome, atypical, susceptibility to, 1 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	- -

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). 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 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	3.7
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

Other links and lift over

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