rs10922093

Variant names:

• chr1-196692051-A-G
• rs10922093
• NM_000186.4:c.1336+1812A>G

Variant summary

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

The NM_000186.4(CFH):​c.1336+1812A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 151,976 control chromosomes in the GnomAD database, including 4,378 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 0.21 (4378 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1336+1812A>G		intron_variant	Intron 9 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.1336+1812A>G		intron_variant	Intron 9 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1336+1812A>G		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1336+1812A>G		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32478 AN: 151862 Hom.: 4375 Cov.: 32

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.214 AC: 32474 AN: 151976 Hom.: 4378 Cov.: 32 AF XY: 0.212 AC XY: 15771 AN XY: 74286

African (AFR) AF: 0.0741 AC: 3076 AN: 41530

American (AMR) AF: 0.273 AC: 4160 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 920 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2615 AN: 5128

South Asian (SAS) AF: 0.229 AC: 1104 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1900 AN: 10524

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17879 AN: 67928

Other (OTH) AF: 0.226 AC: 476 AN: 2110

Alfa AF: 0.238 Hom.: 586

Bravo AF: 0.220

Asia WGS AF: 0.286 AC: 995 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.69
PhyloP100		-0.34
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: rs10922093; hg19: chr1-196661181;