Genetic Variant CFH:c.964+1838A>T (chr1-196687075-A-T) – 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.964+1838A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 151,812 control chromosomes in the GnomAD database, including 30,616 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 0.63 ( 30616 hom., cov: 32)

Consequence

CFH
NM_000186.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.562

Publications

13 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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.964+1838A>T		intron_variant	Intron 7 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 link	c.964+1838A>T		intron_variant	Intron 7 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.964+1838A>T		intron_variant	Intron 7 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1 link	c.964+1838A>T		intron_variant	Intron 7 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes

AF:

0.630

AC:

95547

AN:

151694

Hom.:

30593

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.729

Gnomad ASJ

AF:

0.662

Gnomad EAS

AF:

0.947

Gnomad SAS

AF:

0.720

Gnomad FIN

AF:

0.562

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.618

Gnomad OTH

AF:

0.657

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

GnomAD4 genome

AF:

0.630

AC:

95610

AN:

151812

Hom.:

30616

Cov.:

AF XY:

0.634

AC XY:

47006

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.579

AC:

23968

AN:

41428

American (AMR)

AF:

0.730

AC:

11105

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.662

AC:

2295

AN:

3468

East Asian (EAS)

AF:

0.948

AC:

4878

AN:

5148

South Asian (SAS)

AF:

0.720

AC:

3463

AN:

4810

European-Finnish (FIN)

AF:

0.562

AC:

5927

AN:

10544

Middle Eastern (MID)

AF:

0.656

AC:

193

AN:

294

European-Non Finnish (NFE)

AF:

0.618

AC:

41920

AN:

67876

Other (OTH)

AF:

0.657

AC:

1388

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1767

3535

5302

7070

8837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<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:

0.620

Hom.:

3663

Bravo

AF:

0.643

Asia WGS

AF:

0.778

AC:

2705

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

6.7

(source)

DANN

Benign

0.46

PhyloP100

0.56

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