1-196825510-G-C

Position:

• chr1-196825510-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002113.3(CFHR1):​c.92G>C​(p.Gly31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,582 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: CFHR1 NM_002113.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR1	NM_002113.3	c.92G>C	p.Gly31Ala	missense_variant	2/6	ENST00000320493.10	NP_002104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR1	ENST00000320493.10	c.92G>C	p.Gly31Ala	missense_variant	2/6	1	NM_002113.3	ENSP00000314299.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381582 Hom.: 1 Cov.: 30 AF XY: 0.00000291 AC XY: 2 AN XY: 686176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 08, 2024

Variant summary: CFHR1 c.92G>C (p.Gly31Ala) results in a non-conservative amino acid change located in the Sushi/SCR/CCP domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234880 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.92G>C in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M;.
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.38
Sift	Benign	0.048	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.31
MutPred		0.82		Gain of ubiquitination at K27 (P = 0.1504);Gain of ubiquitination at K27 (P = 0.1504);
MVP		0.81
MPC		0.30
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.53
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: -33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-196794640;