chr1-196994232-T-C

Variant names:

• chr1-196994232-T-C
• NM_030787.4:c.583T>C

Variant summary

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

The NM_030787.4(CFHR5):​c.583T>C​(p.Ser195Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,236 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. S195T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFHR5 NM_030787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11

Genes affected

CFHR5 (HGNC:24668): (complement factor H related 5) This gene is a member of a small complement factor H (CFH) gene cluster on chromosome 1. Each member of this gene family contains multiple short consensus repeats (SCRs) typical of regulators of complement activation. The protein encoded by this gene has nine SCRs with the first two repeats having heparin binding properties, a region within repeats 5-7 having heparin binding and C reactive protein binding properties, and the C-terminal repeats being similar to a complement component 3 b (C3b) binding domain. This protein co-localizes with C3, binds C3b in a dose-dependent manner, and is recruited to tissues damaged by C-reactive protein. Allelic variations in this gene have been associated, but not causally linked, with two different forms of kidney disease: membranoproliferative glomerulonephritis type II (MPGNII) and hemolytic uraemic syndrome (HUS). [provided by RefSeq, Jan 2010]

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 rank	MANE	Protein	UniProt
CFHR5	NM_030787.4	c.583T>C	p.Ser195Pro	missense_variant	Exon 4 of 10	ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3	c.592T>C	p.Ser198Pro	missense_variant	Exon 4 of 10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5	c.583T>C	p.Ser195Pro	missense_variant	Exon 4 of 10	1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699466.1	c.328T>C	p.Ser110Pro	missense_variant	Exon 4 of 10			ENSP00000514393.1
CFHR5	ENST00000699468.1	c.-24-1882T>C		intron_variant	Intron 1 of 5			ENSP00000514394.1
CFHR5	ENST00000699467.1	n.652T>C		non_coding_transcript_exon_variant	Exon 4 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461236 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726950

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.67		Gain of glycosylation at S195 (P = 0.0718);
MVP		0.82
MPC		0.12
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.73
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-196963362;