chr1-196983956-C-T

Variant names:

• chr1-196983956-C-T
• rs185709089
• NM_030787.4:c.254-5C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000256785.5(CFHR5):​c.254-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,601,726 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (19 hom.)
• Consequence: CFHR5 ENST00000256785.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003649
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.06
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-196983956-C-T is Benign according to our data. Variant chr1-196983956-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 599457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 559 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000256785.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	NM_030787.4	MANE Select	c.254-5C>T		splice_region intron	N/A	NP_110414.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	ENST00000256785.5	TSL:1 MANE Select	c.254-5C>T		splice_region intron	N/A	ENSP00000256785.4
	CFHR5	ENST00000699466.1		c.-2-5C>T		splice_region intron	N/A	ENSP00000514393.1
	CFHR5	ENST00000699468.1		c.-25+6276C>T		intron	N/A	ENSP00000514394.1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 558 AN: 151780 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00578

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00731

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00317 AC: 790 AN: 249462 AF XY: 0.00307

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00742

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00447 AC: 6487 AN: 1449832 Hom.: 19 Cov.: 28 AF XY: 0.00432 AC XY: 3118 AN XY: 721592

African (AFR) AF: 0.000662 AC: 22 AN: 33228

American (AMR) AF: 0.00248 AC: 110 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.000539 AC: 14 AN: 25974

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39500

South Asian (SAS) AF: 0.000742 AC: 63 AN: 84962

European-Finnish (FIN) AF: 0.00669 AC: 356 AN: 53192

Middle Eastern (MID) AF: 0.000425 AC: 2 AN: 4702

European-Non Finnish (NFE) AF: 0.00516 AC: 5693 AN: 1103990

Other (OTH) AF: 0.00378 AC: 226 AN: 59864

GnomAD4 genome AF: 0.00368 AC: 559 AN: 151894 Hom.: 1 Cov.: 32 AF XY: 0.00375 AC XY: 278 AN XY: 74226

African (AFR) AF: 0.00101 AC: 42 AN: 41384

American (AMR) AF: 0.00578 AC: 88 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4814

European-Finnish (FIN) AF: 0.00731 AC: 77 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00484 AC: 329 AN: 67956

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00382 Hom.: 0

Bravo AF: 0.00318

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)
-	-	1	CFHR5 deficiency (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.80
DANN	Benign	0.48
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs185709089; hg19: chr1-196953086;