rs16840522

Variant names:

• chr1-196741786-T-C
• rs16840522
• ENST00000466229.5:n.5966T>C

Variant summary

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

The ENST00000466229.5(CFH):​n.5966T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,194,894 control chromosomes in the GnomAD database, including 27,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4486 hom., cov: 33)
  • Exomes 𝑓: 0.20 (23145 hom.)
• Consequence: CFH ENST00000466229.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.670
• Publications: 25 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=-0.89).
• BP6: Variant 1-196741786-T-C is Benign according to our data. Variant chr1-196741786-T-C is described in ClinVar as Benign. ClinVar VariationId is 1228859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2957-89T>C		intron_variant	Intron 18 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2957-89T>C		intron_variant	Intron 18 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2957-89T>C		intron_variant	Intron 18 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34419 AN: 152108 Hom.: 4491 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.0546

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.247

GnomAD4 exome AF: 0.202 AC: 210421 AN: 1042668 Hom.: 23145 Cov.: 14 AF XY: 0.207 AC XY: 110705 AN XY: 535134

African (AFR) AF: 0.345 AC: 8407 AN: 24372

American (AMR) AF: 0.111 AC: 4632 AN: 41718

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 5946 AN: 23022

East Asian (EAS) AF: 0.0558 AC: 2027 AN: 36342

South Asian (SAS) AF: 0.326 AC: 24310 AN: 74674

European-Finnish (FIN) AF: 0.127 AC: 6602 AN: 52048

Middle Eastern (MID) AF: 0.325 AC: 1467 AN: 4514

European-Non Finnish (NFE) AF: 0.199 AC: 147356 AN: 739754

Other (OTH) AF: 0.209 AC: 9674 AN: 46224

GnomAD4 genome AF: 0.226 AC: 34430 AN: 152226 Hom.: 4486 Cov.: 33 AF XY: 0.226 AC XY: 16795 AN XY: 74440

African (AFR) AF: 0.331 AC: 13743 AN: 41514

American (AMR) AF: 0.168 AC: 2565 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 925 AN: 3472

East Asian (EAS) AF: 0.0545 AC: 283 AN: 5192

South Asian (SAS) AF: 0.323 AC: 1562 AN: 4830

European-Finnish (FIN) AF: 0.129 AC: 1371 AN: 10610

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13249 AN: 67996

Other (OTH) AF: 0.248 AC: 525 AN: 2114

Alfa AF: 0.204 Hom.: 497

Bravo AF: 0.229

Asia WGS AF: 0.202 AC: 701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.49
PhyloP100		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16840522; hg19: chr1-196710916; COSMIC: COSV66408666; COSMIC: COSV66408666;