1-196825548-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_002113.3(CFHR1):c.130C>T(p.Gln44Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,521,828 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00049 (22 hom., cov: 24)
  • Exomes 𝑓: 0.000063 (28 hom.)
• Consequence: CFHR1 NM_002113.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.489

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 -2 ACMG points.

• PM4: Stoplost variant in NM_002113.3 Downstream stopcodon found after 368 codons.
• BS2: High Homozygotes in GnomAd at 22 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR1	NM_002113.3	c.130C>T	p.Gln44Ter	stop_gained	2/6	ENST00000320493.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR1	ENST00000320493.10	c.130C>T	p.Gln44Ter	stop_gained	2/6	1	NM_002113.3	P1

Frequencies

GnomAD3 genomes AF: 0.000488 AC: 66 AN: 135174 Hom.: 22 Cov.: 24

Gnomad AFR AF: 0.00199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000508

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 30 AN: 236278 Hom.: 9 AF XY: 0.0000863 AC XY: 11 AN XY: 127400

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000371

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000627 AC: 87 AN: 1386534 Hom.: 28 Cov.: 30 AF XY: 0.0000639 AC XY: 44 AN XY: 688572

Gnomad4 AFR exome AF: 0.00241

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000105

GnomAD4 genome AF: 0.000488 AC: 66 AN: 135294 Hom.: 22 Cov.: 24 AF XY: 0.000380 AC XY: 25 AN XY: 65866

Gnomad4 AFR AF: 0.00198

Gnomad4 AMR AF: 0.0000713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000509

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000927 Hom.: 3

ESP6500AA AF: 0.00299 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000131 AC: 15

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

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.024	N
MutationTaster	Benign	1.0	A;A;N
Vest4		0.49
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs146147352; hg19: chr1-196794678; COSMIC: COSV105825010; COSMIC: COSV105825010;