NM_001201550.3:c.204G>A

Variant names:

• chr1-196902563-G-A
• rs201480125
• NM_001201550.3:c.204G>A

Variant summary

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

The NM_001201550.3(CFHR4):​c.204G>A​(p.Trp68*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,612,170 control chromosomes in the GnomAD database, including 6 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 0.00044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (3 hom.)
• Consequence: CFHR4 NM_001201550.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.01

Genes affected

CFHR4 (HGNC:16979): (complement factor H related 4) This gene is a member of the complement factor H (CFH) gene family, and encodes one of the 5 CFH-related (CFHR) proteins. These 5 genes are closely linked to the CFH gene on chromosome 1q31-q32. The CFHRs are secreted plasma proteins synthesized primarily by the hepatocytes, and composed of highly-related short consensus repeats (SCRs). This protein enhances the cofactor activity of CFH, and is involved in complement regulation. It can associate with lipoproteins and may play a role in lipid metabolism. Alternatively spliced transcript variants encoding different isoforms (varying in the number of SCRs) have been described for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR4	NM_001201550.3	c.204G>A	p.Trp68*	stop_gained	Exon 2 of 10	ENST00000608469.6	NP_001188479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR4	ENST00000608469.6	c.204G>A	p.Trp68*	stop_gained	Exon 2 of 10	1	NM_001201550.3	ENSP00000477162.2

Frequencies

GnomAD3 genomes AF: 0.000430 AC: 65 AN: 151082 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

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: 0.0000736

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.0000800 AC: 20 AN: 250096 Hom.: 1 AF XY: 0.0000295 AC XY: 4 AN XY: 135638

Gnomad AFR exome AF: 0.00103

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1460974 Hom.: 3 Cov.: 30 AF XY: 0.0000633 AC XY: 46 AN XY: 726800

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000594

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000437 AC: 66 AN: 151196 Hom.: 3 Cov.: 32 AF XY: 0.000366 AC XY: 27 AN XY: 73844

Gnomad4 AFR AF: 0.00134

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00162 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFHR4 c.204G>A (p.Trp68X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however, currently available evidence is insufficient to determine whether loss-of-function variants in the CFHR4 gene can cause disease. The variant allele was found at a frequency of 0.00043 in 149854 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. To our knowledge, no occurrence of c.204G>A in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Apr 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.35	N
Vest4		0.21
GERP RS		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs201480125; hg19: chr1-196871693;