rs10489456

Variant names:

• chr1-196718385-G-A
• rs10489456
• NM_000186.4:c.1696+2616G>A

Variant summary

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

The NM_000186.4(CFH):​c.1696+2616G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,136 control chromosomes in the GnomAD database, including 2,559 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 0.16 (2559 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 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.1696+2616G>A		intron	N/A	NP_000177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1696+2616G>A		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1696+2616G>A		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.3712+2616G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24958 AN: 152018 Hom.: 2559 Cov.: 32

Gnomad AFR AF: 0.0990

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.164 AC: 24961 AN: 152136 Hom.: 2559 Cov.: 32 AF XY: 0.165 AC XY: 12280 AN XY: 74374

African (AFR) AF: 0.0990 AC: 4111 AN: 41542

American (AMR) AF: 0.232 AC: 3541 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.483 AC: 2496 AN: 5168

South Asian (SAS) AF: 0.150 AC: 725 AN: 4820

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10592

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11519 AN: 67982

Other (OTH) AF: 0.164 AC: 345 AN: 2110

Alfa AF: 0.164 Hom.: 274

Bravo AF: 0.174

Asia WGS AF: 0.239 AC: 831 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.30
DANN	Benign	0.73
PhyloP100		-1.4
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: rs10489456; hg19: chr1-196687515;