Genetic Variant CFH:c.2414-28C>T (chr1-196736796-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000186.4(CFH):c.2414-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CFH
NM_000186.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.39

Publications

0 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):

C3 glomerulonephritis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
atypical hemolytic-uremic syndrome
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
basal laminar drusen
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hemolytic uremic syndrome, atypical, susceptibility to, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
complement factor H deficiency
Inheritance: AR Classification: STRONG, MODERATE 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.2414-28C>T		intron	N/A	NP_000177.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFH	ENST00000367429.9	TSL:1 MANE Select	c.2414-28C>T	intron	N/A	ENSP00000356399.4	P08603
ENSG00000289697	ENST00000696032.1		c.2414-28C>T	intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
CFH	ENST00000466229.5	TSL:1	n.4430-28C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150344

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000106

AC:

AN:

940632

Hom.:

Cov.:

AF XY:

0.00000216

AC XY:

AN XY:

462564

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19122

American (AMR)

AF:

0.00

AC:

AN:

9780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15816

East Asian (EAS)

AF:

0.0000426

AC:

AN:

23474

South Asian (SAS)

AF:

0.00

AC:

AN:

25846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

773370

Other (OTH)

AF:

0.00

AC:

AN:

38098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73352

African (AFR)

AF:

0.00

AC:

AN:

41224

American (AMR)

AF:

0.00

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67462

Other (OTH)

AF:

0.00

AC:

AN:

2074

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.20

(source)

DANN

Benign

0.66

PhyloP100

-1.4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over