1-196688525-C-T

Variant names:

• chr1-196688525-C-T
• rs10801554
• NM_000186.4:c.965-895C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000186.4(CFH):​c.965-895C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,972 control chromosomes in the GnomAD database, including 32,036 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 0.64 (32036 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• Publications: 11 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):

• 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

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.965-895C>T		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.965-895C>T		intron	N/A	NP_001014975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.965-895C>T		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.965-895C>T		intron	N/A	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.965-895C>T		intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97919 AN: 151854 Hom.: 32012 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.666

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

GnomAD4 genome AF: 0.645 AC: 97984 AN: 151972 Hom.: 32036 Cov.: 32 AF XY: 0.648 AC XY: 48099 AN XY: 74258

African (AFR) AF: 0.629 AC: 26073 AN: 41450

American (AMR) AF: 0.737 AC: 11247 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2297 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4900 AN: 5166

South Asian (SAS) AF: 0.720 AC: 3471 AN: 4822

European-Finnish (FIN) AF: 0.564 AC: 5934 AN: 10530

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41989 AN: 67956

Other (OTH) AF: 0.665 AC: 1406 AN: 2114

Alfa AF: 0.629 Hom.: 3911

Bravo AF: 0.660

Asia WGS AF: 0.780 AC: 2707 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.63
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10801554; hg19: chr1-196657655;