NM_000186.4:c.245-9delT

Variant names:

• chr1-196673839-CT-C
• rs35507625
• NM_000186.4:c.245-9delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000186.4(CFH):​c.245-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,485,816 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 23)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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-CT-C is Benign according to our data. Variant chr1-196673839-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1591064.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 = 0.00393 (594/151260) while in subpopulation AFR AF = 0.0138 (569/41248). AF 95% confidence interval is 0.0129. There are 5 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.245-9delT		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.245-9delT		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.245-9delT		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.245-9delT		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.245-9delT		intron	N/A	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 593 AN: 151146 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000791

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.00289

GnomAD4 exome AF: 0.000553 AC: 738 AN: 1334556 Hom.: 4 Cov.: 25 AF XY: 0.000489 AC XY: 328 AN XY: 670282

African (AFR) AF: 0.0164 AC: 508 AN: 31038

American (AMR) AF: 0.000342 AC: 15 AN: 43808

Ashkenazi Jewish (ASJ) AF: 0.0000796 AC: 2 AN: 25124

East Asian (EAS) AF: 0.0000532 AC: 2 AN: 37590

South Asian (SAS) AF: 0.0000967 AC: 8 AN: 82704

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52492

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5518

European-Non Finnish (NFE) AF: 0.000145 AC: 145 AN: 1000484

Other (OTH) AF: 0.00100 AC: 56 AN: 55798

GnomAD4 genome AF: 0.00393 AC: 594 AN: 151260 Hom.: 5 Cov.: 23 AF XY: 0.00387 AC XY: 286 AN XY: 73822

African (AFR) AF: 0.0138 AC: 569 AN: 41248

American (AMR) AF: 0.000790 AC: 12 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67792

Other (OTH) AF: 0.00286 AC: 6 AN: 2096

Alfa AF: 0.000369 Hom.: 241

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Age related macular degeneration 4 (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	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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35507625; hg19: chr1-196642969;