1-196726612-A-G

Position:

• chr1-196726612-A-G

Variant summary

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

The ENST00000367429.9(CFH):​c.2016A>G​(p.Gln672=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,608,810 control chromosomes in the GnomAD database, including 28,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2399 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26311 hom.)
• Consequence: CFH ENST00000367429.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0700

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-196726612-A-G is Benign according to our data. Variant chr1-196726612-A-G is described in ClinVar as [Benign]. Clinvar id is 294498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196726612-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.2016A>G	p.Gln672=	synonymous_variant	13/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2016A>G	p.Gln672=	synonymous_variant	13/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23159 AN: 152090 Hom.: 2399 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.204 AC: 51150 AN: 250754 Hom.: 6984 AF XY: 0.196 AC XY: 26513 AN XY: 135512

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.505

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.177 AC: 257139 AN: 1456602 Hom.: 26311 Cov.: 32 AF XY: 0.175 AC XY: 126598 AN XY: 724974

Gnomad4 AFR exome AF: 0.0505

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.152 AC: 23152 AN: 152208 Hom.: 2399 Cov.: 32 AF XY: 0.153 AC XY: 11375 AN XY: 74398

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.156

Alfa AF: 0.172 Hom.: 4260

Bravo AF: 0.160

Asia WGS AF: 0.235 AC: 817 AN: 3476

EpiCase AF: 0.170

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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. -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.4
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3753396; hg19: chr1-196695742; COSMIC: COSV66405881;