chr1-196825654-C-A

Variant names:

• chr1-196825654-C-A
• rs754574977
• NM_002113.3:c.236C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_002113.3(CFHR1):​c.236C>A​(p.Pro79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000821 in 1,523,188 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (2 hom., cov: 24)
  • Exomes 𝑓: 0.000084 (16 hom.)
• Consequence: CFHR1 NM_002113.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.817
• Publications: 0 publications found

Genes affected

CFHR1 (HGNC:4888): (complement factor H related 1) This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome. [provided by RefSeq, Oct 2009]

CFHR1 Gene-Disease associations (from GenCC):

• dense deposit disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• age related macular degeneration 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 Unknown,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002113.3. 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
	CFHR1	NM_002113.3	MANE Select	c.236C>A	p.Pro79Gln	missense	Exon 2 of 6	NP_002104.2	Q03591
	CFHR1	NM_001379306.1		c.185C>A	p.Pro62Gln	missense	Exon 2 of 6	NP_001366235.1
	CFHR1	NM_001379307.1		c.74C>A	p.Pro25Gln	missense	Exon 2 of 6	NP_001366236.1	A0A8V8TNS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR1	ENST00000320493.10	TSL:1 MANE Select	c.236C>A	p.Pro79Gln	missense	Exon 2 of 6	ENSP00000314299.5	Q03591
	CFHR1	ENST00000887404.1		c.236C>A	p.Pro79Gln	missense	Exon 2 of 6	ENSP00000557463.1
	CFHR1	ENST00000887414.1		c.209C>A	p.Pro70Gln	missense	Exon 2 of 6	ENSP00000557473.1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 8 AN: 134884 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000124

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000211 AC: 5 AN: 236828 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000462

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000843 AC: 117 AN: 1388304 Hom.: 16 Cov.: 30 AF XY: 0.0000827 AC XY: 57 AN XY: 689318

African (AFR) AF: 0.00 AC: 0 AN: 26672

American (AMR) AF: 0.00 AC: 0 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.0000413 AC: 1 AN: 24190

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 76260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5082

European-Non Finnish (NFE) AF: 0.000107 AC: 114 AN: 1063648

Other (OTH) AF: 0.0000351 AC: 2 AN: 57024

GnomAD4 genome AF: 0.0000593 AC: 8 AN: 134884 Hom.: 2 Cov.: 24 AF XY: 0.0000305 AC XY: 2 AN XY: 65538

African (AFR) AF: 0.00 AC: 0 AN: 31488

American (AMR) AF: 0.00 AC: 0 AN: 13936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3144

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 3900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000124 AC: 8 AN: 64302

Other (OTH) AF: 0.00 AC: 0 AN: 1824

Alfa AF: 0.0000776 Hom.: 0

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000261 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.82
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.23
Sift	Benign	0.55	T
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.35
MVP		0.81
MPC		0.24
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.67
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs754574977; hg19: chr1-196794784; COSMIC: COSV57626816; COSMIC: COSV57626816;