1-196825389-C-A

Variant names:

• chr1-196825389-C-A
• rs442759
• NM_002113.3:c.59-88C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002113.3(CFHR1):​c.59-88C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 888,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: CFHR1 NM_002113.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 0 publications found

Genes affected

CFHR1 (HGNC:4888): (complement factor H related 1) This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome. [provided by RefSeq, Oct 2009]

CFHR1 Gene-Disease associations (from GenCC):

• dense deposit disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• age related macular degeneration 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002113.3. 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
	CFHR1	NM_002113.3	MANE Select	c.59-88C>A		intron	N/A	NP_002104.2	Q03591
	CFHR1	NM_001379306.1		c.59-139C>A		intron	N/A	NP_001366235.1
	CFHR1	NM_001379307.1		c.59-250C>A		intron	N/A	NP_001366236.1	A0A8V8TNS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR1	ENST00000320493.10	TSL:1 MANE Select	c.59-88C>A		intron	N/A	ENSP00000314299.5	Q03591
	CFHR1	ENST00000887404.1		c.59-88C>A		intron	N/A	ENSP00000557463.1
	CFHR1	ENST00000887414.1		c.13-69C>A		intron	N/A	ENSP00000557473.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 888796 Hom.: 0 Cov.: 12 AF XY: 0.00000224 AC XY: 1 AN XY: 447284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14470

American (AMR) AF: 0.00 AC: 0 AN: 26254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17356

East Asian (EAS) AF: 0.00 AC: 0 AN: 33086

South Asian (SAS) AF: 0.00 AC: 0 AN: 51222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2752

European-Non Finnish (NFE) AF: 0.00000151 AC: 1 AN: 663072

Other (OTH) AF: 0.00 AC: 0 AN: 38672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.50
DANN	Benign	0.16
PhyloP100		-1.1

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: rs442759; hg19: chr1-196794519;