1-196699189-A-T

Variant names:

• chr1-196699189-A-T
• rs2860102
• NM_000186.4:c.1336+8950A>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.1336+8950A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,988 control chromosomes in the GnomAD database, including 32,228 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 0.65 (32228 hom., cov: 31)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 9 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 = 0.926 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.1336+8950A>T		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.1337-2129A>T		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+8950A>T		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1336+8950A>T		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.1337-2129A>T		intron	N/A	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98212 AN: 151868 Hom.: 32204 Cov.: 31

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.668

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

GnomAD4 genome AF: 0.647 AC: 98279 AN: 151988 Hom.: 32228 Cov.: 31 AF XY: 0.650 AC XY: 48266 AN XY: 74260

African (AFR) AF: 0.636 AC: 26374 AN: 41464

American (AMR) AF: 0.739 AC: 11273 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2294 AN: 3466

East Asian (EAS) AF: 0.948 AC: 4900 AN: 5168

South Asian (SAS) AF: 0.721 AC: 3473 AN: 4820

European-Finnish (FIN) AF: 0.561 AC: 5929 AN: 10560

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

European-Non Finnish (NFE) AF: 0.618 AC: 41963 AN: 67940

Other (OTH) AF: 0.667 AC: 1406 AN: 2108

Alfa AF: 0.629 Hom.: 3769

Bravo AF: 0.663

Asia WGS AF: 0.781 AC: 2714 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	0.97
DANN	Benign	0.15
PhyloP100		-1.0
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: rs2860102; hg19: chr1-196668319;