rs373258103

Variant names:

• chr1-196779338-C-A
• rs373258103
• NM_021023.6:c.235C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-196779338-C-A
• chr1-196779338-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021023.6(CFHR3):​c.235C>A​(p.Pro79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000396 in 1,515,952 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CFHR3 NM_021023.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

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]

CFHR3 Gene-Disease associations (from GenCC):

• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021023.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR3	NM_021023.6	MANE Select	c.235C>A	p.Pro79Thr	missense	Exon 2 of 6	NP_066303.2	Q02985-1
	CFHR3	NM_001166624.2		c.235C>A	p.Pro79Thr	missense	Exon 2 of 5	NP_001160096.1	Q02985-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR3	ENST00000367425.9	TSL:1 MANE Select	c.235C>A	p.Pro79Thr	missense	Exon 2 of 6	ENSP00000356395.5	Q02985-1
	ENSG00000289697	ENST00000696032.1		c.3757C>A	p.Pro1253Thr	missense	Exon 23 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFHR3	ENST00000471440.6	TSL:1	c.235C>A	p.Pro79Thr	missense	Exon 2 of 5	ENSP00000436258.1	Q6NSD3

Frequencies

GnomAD3 genomes AF: 0.00000734 AC: 1 AN: 136256 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 237866 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000924

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1379696 Hom.: 0 Cov.: 29 AF XY: 0.00000437 AC XY: 3 AN XY: 685978

African (AFR) AF: 0.00 AC: 0 AN: 27322

American (AMR) AF: 0.00 AC: 0 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24252

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 76284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5080

European-Non Finnish (NFE) AF: 0.00000474 AC: 5 AN: 1054012

Other (OTH) AF: 0.00 AC: 0 AN: 56830

GnomAD4 genome AF: 0.00000734 AC: 1 AN: 136256 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 66190

African (AFR) AF: 0.00 AC: 0 AN: 32552

American (AMR) AF: 0.00 AC: 0 AN: 14038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3170

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 3930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64416

Other (OTH) AF: 0.00 AC: 0 AN: 1824

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.00000863 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.66		Gain of glycosylation at P79 (P = 0.0402)
MVP		0.77
MPC		0.51
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.54
gMVP		0.66
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs373258103; hg19: chr1-196748468;