1-196977416-T-C

Position:

• chr1-196977416-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000699466.1(CFHR5):​c.-198+2302T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 500,996 control chromosomes in the GnomAD database, including 6,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4364 hom., cov: 31)
  • Exomes 𝑓: 0.093 (2269 hom.)
• Consequence: CFHR5 ENST00000699466.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.600

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-196977416-T-C is Benign according to our data. Variant chr1-196977416-T-C is described in ClinVar as [Benign]. Clinvar id is 1225260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR5	XM_011510020.3	c.67+2302T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR5	ENST00000699466.1	c.-198+2302T>C		intron_variant
CFHR5	ENST00000699467.1	n.127+1828T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27683 AN: 151924 Hom.: 4357 Cov.: 31

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0895

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.0926 AC: 32312 AN: 348954 Hom.: 2269 AF XY: 0.0921 AC XY: 17367 AN XY: 188564

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.0749

Gnomad4 ASJ exome AF: 0.0842

Gnomad4 EAS exome AF: 0.000144

Gnomad4 SAS exome AF: 0.0991

Gnomad4 FIN exome AF: 0.0623

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.182 AC: 27710 AN: 152042 Hom.: 4364 Cov.: 31 AF XY: 0.179 AC XY: 13337 AN XY: 74308

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0999

Gnomad4 FIN AF: 0.0711

Gnomad4 NFE AF: 0.0895

Gnomad4 OTH AF: 0.164

Alfa AF: 0.0969 Hom.: 1692

Bravo AF: 0.196

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 16299065) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.5
DANN	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9427661; hg19: chr1-196946546;