1-196825463-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002113.3(CFHR1):c.59-14T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,419,434 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (27 hom., cov: 24)
  • Exomes 𝑓: 0.000072 (18 hom.)
• Consequence: CFHR1 NM_002113.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.186

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd at 26 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR1	NM_002113.3	c.59-14T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320493.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR1	ENST00000320493.10	c.59-14T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002113.3	P1

Frequencies

GnomAD3 genomes AF: 0.000576 AC: 78 AN: 135502 Hom.: 26 Cov.: 24

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000214

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000155

Gnomad OTH AF: 0.000549

GnomAD3 exomes AF: 0.000112 AC: 25 AN: 223522 Hom.: 8 AF XY: 0.0000993 AC XY: 12 AN XY: 120798

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000298

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000717 AC: 92 AN: 1283814 Hom.: 18 Cov.: 27 AF XY: 0.0000717 AC XY: 46 AN XY: 641334

Gnomad4 AFR exome AF: 0.00193

Gnomad4 AMR exome AF: 0.0000697

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000287

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000605 AC: 82 AN: 135620 Hom.: 27 Cov.: 24 AF XY: 0.000576 AC XY: 38 AN XY: 65944

Gnomad4 AFR AF: 0.00242

Gnomad4 AMR AF: 0.000213

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000155

Gnomad4 OTH AF: 0.000543

Alfa AF: 0.000506 Hom.: 2

Asia WGS AF: 0.000931 AC: 3 AN: 3236

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.072
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 14

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

Publications

LitVar

Other links and lift over

dbSNP: rs113307454; hg19: chr1-196794593;