1-196977416-T-C

Variant names:

• chr1-196977416-T-C
• rs9427661
• ENST00000699466.1:c.-198+2302T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

CFHR5 Gene-Disease associations (from GenCC):

• C3 glomerulonephritis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CFHR5	XM_011510020.3	c.67+2302T>C		intron_variant	Intron 1 of 9		XP_011508322.1
CFHR5	NM_030787.4	c.-249T>C		upstream_gene_variant		ENST00000256785.5	NP_110414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000699466.1	c.-198+2302T>C		intron_variant	Intron 1 of 9			ENSP00000514393.1
CFHR5	ENST00000699467.1	n.127+1828T>C		intron_variant	Intron 1 of 9
CFHR5	ENST00000256785.5	c.-249T>C		upstream_gene_variant		1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699468.1	c.-289T>C		upstream_gene_variant				ENSP00000514394.1

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

African (AFR) AF: 0.427 AC: 4132 AN: 9668

American (AMR) AF: 0.0749 AC: 1209 AN: 16136

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 838 AN: 9950

East Asian (EAS) AF: 0.000144 AC: 3 AN: 20884

South Asian (SAS) AF: 0.0991 AC: 4374 AN: 44140

European-Finnish (FIN) AF: 0.0623 AC: 1366 AN: 21938

Middle Eastern (MID) AF: 0.138 AC: 193 AN: 1398

European-Non Finnish (NFE) AF: 0.0885 AC: 18200 AN: 205592

Other (OTH) AF: 0.104 AC: 1997 AN: 19248

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

African (AFR) AF: 0.433 AC: 17928 AN: 41420

American (AMR) AF: 0.114 AC: 1742 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0999 AC: 480 AN: 4804

European-Finnish (FIN) AF: 0.0711 AC: 752 AN: 10582

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0895 AC: 6088 AN: 67986

Other (OTH) AF: 0.164 AC: 346 AN: 2112

Alfa AF: 0.123 Hom.: 5199

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.60
PromoterAI		0.017	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs9427661; hg19: chr1-196946546;