1-196673839-CTT-CTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000186.4(CFH):c.245-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,478,290 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 23)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

CFH
NM_000186.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0950

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 1-196673839-C-CT is Benign according to our data. Variant chr1-196673839-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1553720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00322 (487/151258) while in subpopulation AFR AF = 0.0109 (448/41252). AF 95% confidence interval is 0.01. There are 3 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR,Unknown,SD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.245-9dupT		splice_region intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.245-9dupT		splice_region intron	N/A	NP_001014975.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CFH	ENST00000367429.9	TSL:1 MANE Select	c.245-9dupT	splice_region intron	N/A	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1		c.245-9dupT	splice_region intron	N/A	ENSP00000512341.1
CFH	ENST00000630130.2	TSL:1	c.245-9dupT	splice_region intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

488

AN:

151144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00119

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00289

GnomAD4 exome

AF:

0.00141

AC:

1872

AN:

1327032

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

862

AN XY:

666232

show subpopulations

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

African (AFR)

AF:

0.0128

AC:

396

AN:

30922

American (AMR)

AF:

0.00150

AC:

AN:

43344

Ashkenazi Jewish (ASJ)

AF:

0.000480

AC:

AN:

24980

East Asian (EAS)

AF:

0.00256

AC:

AN:

36714

South Asian (SAS)

AF:

0.000967

AC:

AN:

81682

European-Finnish (FIN)

AF:

0.000480

AC:

AN:

52080

Middle Eastern (MID)

AF:

0.000363

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.00110

AC:

1093

AN:

996306

Other (OTH)

AF:

0.00191

AC:

106

AN:

55498

⚠️ 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: 0.323

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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

AF:

0.00322

AC:

487

AN:

151258

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

230

AN XY:

73824

show subpopulations

African (AFR)

AF:

0.0109

AC:

448

AN:

41252

American (AMR)

AF:

0.00118

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00117

AC:

AN:

5120

South Asian (SAS)

AF:

0.000627

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000885

AC:

AN:

67786

Other (OTH)

AF:

0.00286

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00244

Hom.:

241

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Dec 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Factor H deficiency

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Basal laminar drusen

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Age related macular degeneration 4

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.095

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over