1-196693329-T-C

Variant names:

• chr1-196693329-T-C
• rs10922096
• NM_000186.4:c.1336+3090T>C

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+3090T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 151,848 control chromosomes in the GnomAD database, including 15,551 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 0.42 (15551 hom., cov: 30)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.302
• Publications: 14 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 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.1336+3090T>C		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.1336+3090T>C		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.1336+3090T>C		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1336+3090T>C		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.1336+3090T>C		intron	N/A	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64470 AN: 151730 Hom.: 15538 Cov.: 30

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.425 AC: 64510 AN: 151848 Hom.: 15551 Cov.: 30 AF XY: 0.429 AC XY: 31806 AN XY: 74172

African (AFR) AF: 0.211 AC: 8737 AN: 41442

American (AMR) AF: 0.592 AC: 8996 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1812 AN: 3472

East Asian (EAS) AF: 0.870 AC: 4453 AN: 5118

South Asian (SAS) AF: 0.460 AC: 2216 AN: 4822

European-Finnish (FIN) AF: 0.441 AC: 4655 AN: 10552

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32195 AN: 67924

Other (OTH) AF: 0.446 AC: 942 AN: 2114

Alfa AF: 0.461 Hom.: 28962

Bravo AF: 0.434

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.7
DANN	Benign	0.45
PhyloP100		-0.30
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: rs10922096; hg19: chr1-196662459;