1-196651787-C-T

Variant names:

• chr1-196651787-C-T
• rs3753394
• ENST00000359637:c.-331C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000359637(CFH):​c.-331C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 327,434 control chromosomes in the GnomAD database, including 12,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5012 hom., cov: 32)
  • Exomes 𝑓: 0.28 (7884 hom.)
• Consequence: CFH ENST00000359637 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.312

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-196651787-C-T is Benign according to our data. Variant chr1-196651787-C-T is described in ClinVar as [Benign]. Clinvar id is 1249325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196651787-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000359637	c.-331C>T		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000352658.2
CFH	ENST00000695968.1	c.-331C>T		upstream_gene_variant				ENSP00000512295.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34633 AN: 151936 Hom.: 5008 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.282 AC: 49479 AN: 175378 Hom.: 7884 AF XY: 0.283 AC XY: 26111 AN XY: 92422

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.342

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.516

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.228 AC: 34627 AN: 152056 Hom.: 5012 Cov.: 32 AF XY: 0.226 AC XY: 16832 AN XY: 74314

Gnomad4 AFR AF: 0.0744

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.528

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.251

Alfa AF: 0.286 Hom.: 11407

Bravo AF: 0.232

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14583443, 21868097) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CFH-related disorder Benign:1

Mar 06, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.76

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3753394; hg19: chr1-196620917;