Genetic Variant CFH:c.1336+3090T>C (chr1-196693329-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.1336+3090T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 151,848 control chromosomes in the GnomAD database, including 15,551 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 0.42 ( 15551 hom., cov: 30)

Consequence

CFH
NM_000186.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.302

Publications

14 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 (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.1336+3090T>C		intron_variant	Intron 9 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 link	c.1336+3090T>C		intron_variant	Intron 9 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.1336+3090T>C		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1 link	c.1336+3090T>C		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes

AF:

0.425

AC:

64470

AN:

151730

Hom.:

15538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.591

Gnomad ASJ

AF:

0.522

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.474

Gnomad OTH

AF:

0.446

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

GnomAD4 genome

AF:

0.425

AC:

64510

AN:

151848

Hom.:

15551

Cov.:

AF XY:

0.429

AC XY:

31806

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.211

AC:

8737

AN:

41442

American (AMR)

AF:

0.592

AC:

8996

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.522

AC:

1812

AN:

3472

East Asian (EAS)

AF:

0.870

AC:

4453

AN:

5118

South Asian (SAS)

AF:

0.460

AC:

2216

AN:

4822

European-Finnish (FIN)

AF:

0.441

AC:

4655

AN:

10552

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.474

AC:

32195

AN:

67924

Other (OTH)

AF:

0.446

AC:

942

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1702

3405

5107

6810

8512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.461

Hom.:

28962

Bravo

AF:

0.434

Asia WGS

AF:

0.600

AC:

2087

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

5.7

(source)

DANN

Benign

0.45

PhyloP100

-0.30

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