1-196828162-G-C

Variant names:

• chr1-196828162-G-C
• rs388862
• NM_002113.3:c.523G>C

Variant summary

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

The NM_002113.3(CFHR1):​c.523G>C​(p.Glu175Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 959,468 control chromosomes in the GnomAD database, including 50,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1934 hom., cov: 12)
  • Exomes 𝑓: 0.13 (48367 hom.)
• Consequence: CFHR1 NM_002113.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0750
• Publications: 14 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
• age related macular degeneration 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018653035).
• BP6: Variant 1-196828162-G-C is Benign according to our data. Variant chr1-196828162-G-C is described in ClinVar as Benign. ClinVar VariationId is 1241507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 1934 Unknown,AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR1	NM_002113.3	MANE Select	c.523G>C	p.Glu175Gln	missense	Exon 4 of 6	NP_002104.2
	CFHR1	NM_001379306.1		c.472G>C	p.Glu158Gln	missense	Exon 4 of 6	NP_001366235.1
	CFHR1	NM_001379307.1		c.361G>C	p.Glu121Gln	missense	Exon 4 of 6	NP_001366236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR1	ENST00000320493.10	TSL:1 MANE Select	c.523G>C	p.Glu175Gln	missense	Exon 4 of 6	ENSP00000314299.5
	CFHR1	ENST00000699454.1		c.361G>C	p.Glu121Gln	missense	Exon 4 of 6	ENSP00000514391.1
	CFHR1	ENST00000699455.1		c.280G>C	p.Glu94Gln	missense	Exon 3 of 5	ENSP00000514392.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 11828 AN: 72534 Hom.: 1919 Cov.: 12

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0651

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.113 AC: 18709 AN: 165808 AF XY: 0.112

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0804

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.129 AC: 114031 AN: 886852 Hom.: 48367 Cov.: 30 AF XY: 0.132 AC XY: 58826 AN XY: 444486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.244 AC: 3462 AN: 14212

American (AMR) AF: 0.243 AC: 7322 AN: 30146

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 3648 AN: 14996

East Asian (EAS) AF: 0.373 AC: 9075 AN: 24348

South Asian (SAS) AF: 0.170 AC: 8881 AN: 52354

European-Finnish (FIN) AF: 0.152 AC: 5737 AN: 37718

Middle Eastern (MID) AF: 0.103 AC: 345 AN: 3348

European-Non Finnish (NFE) AF: 0.103 AC: 69582 AN: 673476

Other (OTH) AF: 0.165 AC: 5979 AN: 36254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.163 AC: 11862 AN: 72616 Hom.: 1934 Cov.: 12 AF XY: 0.160 AC XY: 5585 AN XY: 34944

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.181 AC: 2496 AN: 13802

American (AMR) AF: 0.217 AC: 1436 AN: 6630

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 317 AN: 1614

East Asian (EAS) AF: 0.282 AC: 695 AN: 2466

South Asian (SAS) AF: 0.119 AC: 260 AN: 2178

European-Finnish (FIN) AF: 0.146 AC: 904 AN: 6208

Middle Eastern (MID) AF: 0.186 AC: 29 AN: 156

European-Non Finnish (NFE) AF: 0.146 AC: 5520 AN: 37922

Other (OTH) AF: 0.172 AC: 158 AN: 918

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.431 Hom.: 1645

ExAC AF: 0.215 AC: 23240

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

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.8
DANN	Benign	0.55
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.075
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.067
Sift	Benign	0.35	T
Sift4G	Benign	0.29	T
Polyphen		0.12	B
Vest4		0.042
MPC		0.86
ClinPred		0.0040	T
GERP RS		-3.7
Varity_R		0.11
gMVP		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs388862; hg19: chr1-196797292; COSMIC: COSV57625798; COSMIC: COSV57625798;