1-196673839-CTT-CTTTT

Variant names:

• chr1-196673839-C-CTT
• rs35507625
• NM_000186.4:c.245-10_245-9dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000186.4(CFH):​c.245-10_245-9dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,480,524 control chromosomes in the GnomAD database, including 29,687 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4702 hom., cov: 23)
  • Exomes 𝑓: 0.23 (24985 hom.)
• Consequence: CFH NM_000186.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0950
• Publications: 4 publications found

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

ENSG00000289697 (HGNC:):

ACMG classification

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

• BP6: Variant 1-196673839-C-CTT is Benign according to our data. Variant chr1-196673839-C-CTT is described in ClinVar as Benign. ClinVar VariationId is 1166414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

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.245-10_245-9dupTT		splice_region intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.245-10_245-9dupTT		splice_region intron	N/A	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.245-10_245-9dupTT		splice_region intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.245-10_245-9dupTT		splice_region intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.245-10_245-9dupTT		splice_region intron	N/A	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36634 AN: 150994 Hom.: 4684 Cov.: 23

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.226 AC: 300352 AN: 1329416 Hom.: 24985 Cov.: 25 AF XY: 0.228 AC XY: 152069 AN XY: 667864

African (AFR) AF: 0.173 AC: 5352 AN: 30896

American (AMR) AF: 0.290 AC: 12620 AN: 43514

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6085 AN: 25018

East Asian (EAS) AF: 0.429 AC: 16089 AN: 37504

South Asian (SAS) AF: 0.285 AC: 23403 AN: 82242

European-Finnish (FIN) AF: 0.270 AC: 14118 AN: 52378

Middle Eastern (MID) AF: 0.156 AC: 860 AN: 5502

European-Non Finnish (NFE) AF: 0.210 AC: 209186 AN: 996762

Other (OTH) AF: 0.227 AC: 12639 AN: 55600

GnomAD4 genome AF: 0.243 AC: 36700 AN: 151108 Hom.: 4702 Cov.: 23 AF XY: 0.249 AC XY: 18396 AN XY: 73738

African (AFR) AF: 0.188 AC: 7746 AN: 41214

American (AMR) AF: 0.314 AC: 4768 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3458

East Asian (EAS) AF: 0.496 AC: 2539 AN: 5118

South Asian (SAS) AF: 0.329 AC: 1571 AN: 4778

European-Finnish (FIN) AF: 0.281 AC: 2902 AN: 10320

Middle Eastern (MID) AF: 0.145 AC: 42 AN: 290

European-Non Finnish (NFE) AF: 0.228 AC: 15428 AN: 67754

Other (OTH) AF: 0.247 AC: 517 AN: 2094

Alfa AF: 0.142 Hom.: 241

Bravo AF: 0.243

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Age related macular degeneration 4 (1)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Basal laminar drusen (1)
-	-	1	Factor H deficiency (1)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)
-	-	1	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.095
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35507625; hg19: chr1-196642969;