1-196673839-CTT-CTTTTT

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.245-11_245-9dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,479,616 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 7 hom., cov: 23)

Exomes 𝑓: 0.0026 ( 8 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):

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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-196673839-C-CTTT is Benign according to our data. Variant chr1-196673839-C-CTTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1168607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00159 (240/151262) while in subpopulation AMR AF = 0.0131 (199/15190). AF 95% confidence interval is 0.0116. There are 7 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.245-11_245-9dupTTT		splice_region intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.245-11_245-9dupTTT		splice_region intron	N/A	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFH	ENST00000367429.9	TSL:1 MANE Select	c.245-11_245-9dupTTT	splice_region intron	N/A	ENSP00000356399.4	P08603
ENSG00000289697	ENST00000696032.1		c.245-11_245-9dupTTT	splice_region intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
CFH	ENST00000630130.2	TSL:1	c.245-11_245-9dupTTT	splice_region intron	N/A	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

239

AN:

151148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000559

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00145

GnomAD4 exome

AF:

0.00262

AC:

3483

AN:

1328354

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1542

AN XY:

666934

show subpopulations

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

African (AFR)

AF:

0.00110

AC:

AN:

30946

American (AMR)

AF:

0.0341

AC:

1475

AN:

43306

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

24946

East Asian (EAS)

AF:

0.00309

AC:

113

AN:

36594

South Asian (SAS)

AF:

0.00152

AC:

124

AN:

81700

European-Finnish (FIN)

AF:

0.00130

AC:

AN:

52134

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.00152

AC:

1516

AN:

997706

Other (OTH)

AF:

0.00209

AC:

116

AN:

55512

⚠️ 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: 0.311

Heterozygous variant carriers

267

534

800

1067

1334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00159

AC:

240

AN:

151262

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

125

AN XY:

73824

show subpopulations

African (AFR)

AF:

0.000558

AC:

AN:

41252

American (AMR)

AF:

0.0131

AC:

199

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5118

South Asian (SAS)

AF:

0.000418

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67790

Other (OTH)

AF:

0.00143

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.00267

Hom.:

241

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Age related macular degeneration 4 (1)

Atypical hemolytic-uremic syndrome (1)

Basal laminar drusen (1)

Factor H deficiency (1)

Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.095

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over