1-196825654-C-T

Variant names:

• chr1-196825654-C-T
• rs754574977
• NM_002113.3:c.236C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002113.3(CFHR1):​c.236C>T​(p.Pro79Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,388,304 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P79Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000022 (1 hom.)
• Consequence: CFHR1 NM_002113.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.236C>T	p.Pro79Leu	missense	Exon 2 of 6	NP_002104.2	Q03591
	CFHR1	NM_001379306.1		c.185C>T	p.Pro62Leu	missense	Exon 2 of 6	NP_001366235.1
	CFHR1	NM_001379307.1		c.74C>T	p.Pro25Leu	missense	Exon 2 of 6	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.236C>T	p.Pro79Leu	missense	Exon 2 of 6	ENSP00000314299.5	Q03591
	CFHR1	ENST00000887404.1		c.236C>T	p.Pro79Leu	missense	Exon 2 of 6	ENSP00000557463.1
	CFHR1	ENST00000887414.1		c.209C>T	p.Pro70Leu	missense	Exon 2 of 6	ENSP00000557473.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1388304 Hom.: 1 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689318

⚠️ 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: 26672

American (AMR) AF: 0.00 AC: 0 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24190

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 76260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5082

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1063648

Other (OTH) AF: 0.00 AC: 0 AN: 57024

⚠️ 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.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.82
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.23
Sift	Benign	0.51	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.28
MutPred		0.65		Gain of catalytic residue at P79 (P = 0.019)
MVP		0.83
MPC		0.21
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.18
gMVP		0.71
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754574977; hg19: chr1-196794784;