1-196741027-C-T

Variant names:

• chr1-196741027-C-T
• rs11582939
• ENST00000466229.5:n.5207C>T

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.5207C>T 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 0.18 in 518,106 control chromosomes in the GnomAD database, including 10,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2523 hom., cov: 32)
  • Exomes 𝑓: 0.19 (7831 hom.)
• Consequence: CFH ENST00000466229.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.34
• Publications: 14 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=-0.81).
• BP6: Variant 1-196741027-C-T is Benign according to our data. Variant chr1-196741027-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2956+235C>T		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.2956+235C>T		intron_variant	Intron 18 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2956+235C>T		intron_variant	Intron 18 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24623 AN: 152034 Hom.: 2523 Cov.: 32

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.188 AC: 68777 AN: 365954 Hom.: 7831 Cov.: 4 AF XY: 0.185 AC XY: 36123 AN XY: 195756

African (AFR) AF: 0.0896 AC: 971 AN: 10840

American (AMR) AF: 0.293 AC: 4841 AN: 16542

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 1356 AN: 11024

East Asian (EAS) AF: 0.476 AC: 11078 AN: 23264

South Asian (SAS) AF: 0.142 AC: 6052 AN: 42700

European-Finnish (FIN) AF: 0.142 AC: 2689 AN: 18996

Middle Eastern (MID) AF: 0.144 AC: 223 AN: 1548

European-Non Finnish (NFE) AF: 0.172 AC: 37787 AN: 219964

Other (OTH) AF: 0.179 AC: 3780 AN: 21076

GnomAD4 genome AF: 0.162 AC: 24623 AN: 152152 Hom.: 2523 Cov.: 32 AF XY: 0.163 AC XY: 12110 AN XY: 74388

African (AFR) AF: 0.0894 AC: 3710 AN: 41506

American (AMR) AF: 0.229 AC: 3507 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2485 AN: 5156

South Asian (SAS) AF: 0.150 AC: 725 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1528 AN: 10596

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11624 AN: 67982

Other (OTH) AF: 0.163 AC: 345 AN: 2116

Alfa AF: 0.171 Hom.: 2360

Bravo AF: 0.172

Asia WGS AF: 0.237 AC: 823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		1.3
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: rs11582939; hg19: chr1-196710157;