1-196651787-C-T

Variant names:

• chr1-196651787-C-T
• rs3753394
• ENST00000359637.3:c.-331C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000359637.3(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 ENST00000359637.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.312
• Publications: 116 publications found

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 Gene-Disease associations (from GenCC):

• primary membranoproliferative glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• basal laminar drusen

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dense deposit disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.
• 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
ENSG00000289697	ENST00000696032.1	c.-331C>T		upstream_gene_variant				ENSP00000512341.1

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

African (AFR) AF: 0.0690 AC: 428 AN: 6202

American (AMR) AF: 0.342 AC: 2461 AN: 7206

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1582 AN: 5428

East Asian (EAS) AF: 0.516 AC: 5551 AN: 10756

South Asian (SAS) AF: 0.260 AC: 5439 AN: 20942

European-Finnish (FIN) AF: 0.188 AC: 1420 AN: 7536

Middle Eastern (MID) AF: 0.258 AC: 198 AN: 766

European-Non Finnish (NFE) AF: 0.279 AC: 29640 AN: 106382

Other (OTH) AF: 0.272 AC: 2760 AN: 10160

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

African (AFR) AF: 0.0744 AC: 3091 AN: 41522

American (AMR) AF: 0.277 AC: 4228 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3464

East Asian (EAS) AF: 0.528 AC: 2719 AN: 5154

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4822

European-Finnish (FIN) AF: 0.185 AC: 1955 AN: 10566

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19487 AN: 67950

Other (OTH) AF: 0.251 AC: 529 AN: 2106

Alfa AF: 0.276 Hom.: 21308

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
PhyloP100		-0.31
PromoterAI		0.0025	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3753394; hg19: chr1-196620917;