1-196793323-G-A

Position:

• chr1-196793323-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021023.6(CFHR3):​c.803G>A​(p.Cys268Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,372,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. C268F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CFHR3 NM_021023.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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]

ENSG00000289697 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR3	NM_021023.6	c.803G>A	p.Cys268Tyr	missense_variant	6/6	ENST00000367425.9	NP_066303.2
CFHR3	NM_001166624.2	c.620G>A	p.Cys207Tyr	missense_variant	5/5		NP_001160096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR3	ENST00000367425.9	c.803G>A	p.Cys268Tyr	missense_variant	6/6	1	NM_021023.6	ENSP00000356395.5
ENSG00000289697	ENST00000696032.1	c.4325G>A	p.Cys1442Tyr	missense_variant	27/27			ENSP00000512341.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000429 AC: 1 AN: 233198 Hom.: 0 AF XY: 0.00000794 AC XY: 1 AN XY: 125936

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 SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372742 Hom.: 0 Cov.: 30 AF XY: 0.00000440 AC XY: 3 AN XY: 681190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000396

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.061	T;D
Sift4G	Uncertain	0.039	D;D
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.77		Loss of loop (P = 0.1242);.;
MVP		0.97
MPC		0.037
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.26
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs745503234; hg19: chr1-196762453;