1-196779305-G-T

Variant names:

• chr1-196779305-G-T
• rs756348984
• NM_021023.6:c.202G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021023.6(CFHR3):​c.202G>T​(p.Asp68Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. D68N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CFHR3 NM_021023.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31355065).

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.202G>T	p.Asp68Tyr	missense	Exon 2 of 6	NP_066303.2	Q02985-1
	CFHR3	NM_001166624.2		c.202G>T	p.Asp68Tyr	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.202G>T	p.Asp68Tyr	missense	Exon 2 of 6	ENSP00000356395.5	Q02985-1
	ENSG00000289697	ENST00000696032.1		c.3724G>T	p.Asp1242Tyr	missense	Exon 23 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFHR3	ENST00000471440.6	TSL:1	c.202G>T	p.Asp68Tyr	missense	Exon 2 of 5	ENSP00000436258.1	Q6NSD3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393118 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691878

African (AFR) AF: 0.00 AC: 0 AN: 27728

American (AMR) AF: 0.00 AC: 0 AN: 43992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24364

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 76656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5112

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065962

Other (OTH) AF: 0.00 AC: 0 AN: 57316

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.022
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.56		Loss of catalytic residue at D68 (P = 0.0432)
MVP		0.69
MPC		0.54
ClinPred		0.92	D
GERP RS		-0.73
Varity_R		0.46
gMVP		0.82
Mutation Taster		=92/8	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: rs756348984; hg19: chr1-196748435;