Genetic Variant CFH:c.791-2362T>C (chr1-196682702-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000186.4(CFH):c.791-2362T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 151,462 control chromosomes in the GnomAD database, including 4,695 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4695 hom., cov: 32)

Consequence

CFH
NM_000186.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.685

Publications

46 publications found

Variant links:

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

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.791-2362T>C		intron_variant	Intron 6 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 link	c.791-2362T>C		intron_variant	Intron 6 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.791-2362T>C		intron_variant	Intron 6 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1 link	c.791-2362T>C		intron_variant	Intron 6 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32619

AN:

151346

Hom.:

4694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.0778

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.202

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.217

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.216

AC:

32643

AN:

151462

Hom.:

4695

Cov.:

AF XY:

0.215

AC XY:

15892

AN XY:

74028

show subpopulations

African (AFR)

AF:

0.405

AC:

16745

AN:

41368

American (AMR)

AF:

0.144

AC:

2185

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

484

AN:

3452

East Asian (EAS)

AF:

0.0776

AC:

400

AN:

5154

South Asian (SAS)

AF:

0.261

AC:

1258

AN:

4820

European-Finnish (FIN)

AF:

0.120

AC:

1271

AN:

10580

Middle Eastern (MID)

AF:

0.190

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.143

AC:

9682

AN:

67608

Other (OTH)

AF:

0.216

AC:

455

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1160

2319

3479

4638

5798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.159

Hom.:

2710

Bravo

AF:

0.222

Asia WGS

AF:

0.179

AC:

615

AN:

3442

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.0

(source)

DANN

Benign

0.75

PhyloP100

-0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over