chr1-196779209-G-T

Position:

• chr1-196779209-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021023.6(CFHR3):​c.106G>T​(p.Glu36Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000215 in 1,393,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CFHR3 NM_021023.6 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

CFHR3 (HGNC:16980): (complement factor H related 3) The protein encoded by this gene is a secreted protein, which belongs to the complement factor H-related protein family. It binds to heparin, and may be involved in complement regulation. Mutations in this gene are associated with decreased risk of age-related macular degeneration, and with an increased risk of atypical hemolytic-uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR3	NM_021023.6	c.106G>T	p.Glu36Ter	stop_gained	2/6	ENST00000367425.9
CFHR3	NM_001166624.2	c.106G>T	p.Glu36Ter	stop_gained	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR3	ENST00000367425.9	c.106G>T	p.Glu36Ter	stop_gained	2/6	1	NM_021023.6	P1
CFHR3	ENST00000471440.6	c.106G>T	p.Glu36Ter	stop_gained	2/5	1
CFHR3	ENST00000391985.7	c.106G>T	p.Glu36Ter	stop_gained	2/5	2
CFHR3	ENST00000367427.7	c.106G>T	p.Glu36Ter	stop_gained, NMD_transcript_variant	2/7	5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238176 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1393010 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000682

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.: 25

Bravo AF: 0.00000378

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

Nov 25, 2022

Variant summary: CFHR3 c.106G>T (p.Glu36X) 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. Other truncations within this gene have been classified as variants of uncertain significance internally and in ClinVar. The variant allele was found at a frequency of 4.2e-06 in 238176 control chromosomes (gnomAD). 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.106G>T 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	0.085
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.083	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.81
GERP RS		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.50		Position offset: -47

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

Publications

LitVar

Other links and lift over

dbSNP: rs748096320; hg19: chr1-196748339;