NM_002113.3:c.588A>G

Variant names:

• chr1-196828227-A-G
• rs3201739
• NM_002113.3:c.588A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002113.3(CFHR1):​c.588A>G​(p.Thr196Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 937,300 control chromosomes in the GnomAD database, including 51,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4307 hom., cov: 14)
  • Exomes 𝑓: 0.14 (47109 hom.)
• Consequence: CFHR1 NM_002113.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0760
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-196828227-A-G is Benign according to our data. Variant chr1-196828227-A-G is described in ClinVar as Benign. ClinVar VariationId is 1283250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.076 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4307 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.588A>G	p.Thr196Thr	synonymous	Exon 4 of 6	NP_002104.2
	CFHR1	NM_001379306.1		c.537A>G	p.Thr179Thr	synonymous	Exon 4 of 6	NP_001366235.1
	CFHR1	NM_001379307.1		c.426A>G	p.Thr142Thr	synonymous	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.588A>G	p.Thr196Thr	synonymous	Exon 4 of 6	ENSP00000314299.5
	CFHR1	ENST00000699454.1		c.426A>G	p.Thr142Thr	synonymous	Exon 4 of 6	ENSP00000514391.1
	CFHR1	ENST00000699455.1		c.345A>G	p.Thr115Thr	synonymous	Exon 3 of 5	ENSP00000514392.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 20455 AN: 83704 Hom.: 4282 Cov.: 14

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.158 AC: 25983 AN: 164024 AF XY: 0.158

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.137 AC: 116548 AN: 853482 Hom.: 47109 Cov.: 29 AF XY: 0.141 AC XY: 60287 AN XY: 428190

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

African (AFR) AF: 0.241 AC: 3303 AN: 13706

American (AMR) AF: 0.269 AC: 7955 AN: 29610

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 3688 AN: 14704

East Asian (EAS) AF: 0.353 AC: 8257 AN: 23376

South Asian (SAS) AF: 0.189 AC: 9775 AN: 51636

European-Finnish (FIN) AF: 0.158 AC: 5799 AN: 36606

Middle Eastern (MID) AF: 0.103 AC: 336 AN: 3256

European-Non Finnish (NFE) AF: 0.111 AC: 71650 AN: 645622

Other (OTH) AF: 0.165 AC: 5785 AN: 34966

⚠️ 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: 0.245 AC: 20513 AN: 83818 Hom.: 4307 Cov.: 14 AF XY: 0.242 AC XY: 9799 AN XY: 40532

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

African (AFR) AF: 0.269 AC: 4378 AN: 16266

American (AMR) AF: 0.314 AC: 2505 AN: 7978

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 525 AN: 1880

East Asian (EAS) AF: 0.389 AC: 1190 AN: 3062

South Asian (SAS) AF: 0.179 AC: 432 AN: 2420

European-Finnish (FIN) AF: 0.192 AC: 1321 AN: 6886

Middle Eastern (MID) AF: 0.233 AC: 42 AN: 180

European-Non Finnish (NFE) AF: 0.226 AC: 9794 AN: 43330

Other (OTH) AF: 0.236 AC: 245 AN: 1036

⚠️ 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: 0.423 Hom.: 2111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.4
DANN	Benign	0.70
PhyloP100		-0.076
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: rs3201739; hg19: chr1-196797357; COSMIC: COSV57626314; COSMIC: COSV57626314;