1-196831948-A-T

Variant names:

• chr1-196831948-A-T
• rs414628
• NM_002113.3:c.942A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002113.3(CFHR1):​c.942A>T​(p.Arg314Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,521,694 control chromosomes in the GnomAD database, including 200,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (17895 hom., cov: 24)
  • Exomes 𝑓: 0.42 (182210 hom.)
• Consequence: CFHR1 NM_002113.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-196831948-A-T is Benign according to our data. Variant chr1-196831948-A-T is described in ClinVar as Benign. ClinVar VariationId is 1233842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR1	NM_002113.3	c.942A>T	p.Arg314Arg	synonymous_variant	Exon 6 of 6	ENST00000320493.10	NP_002104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR1	ENST00000320493.10	c.942A>T	p.Arg314Arg	synonymous_variant	Exon 6 of 6	1	NM_002113.3	ENSP00000314299.5

Frequencies

GnomAD3 genomes AF: 0.422 AC: 56317 AN: 133544 Hom.: 17874 Cov.: 24

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.438 AC: 103564 AN: 236238 AF XY: 0.436

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.524

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.436

GnomAD4 exome AF: 0.422 AC: 586307 AN: 1388030 Hom.: 182210 Cov.: 34 AF XY: 0.423 AC XY: 291264 AN XY: 689144

African (AFR) AF: 0.369 AC: 9710 AN: 26322

American (AMR) AF: 0.516 AC: 22613 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 12362 AN: 24182

East Asian (EAS) AF: 0.514 AC: 20310 AN: 39482

South Asian (SAS) AF: 0.420 AC: 32040 AN: 76248

European-Finnish (FIN) AF: 0.390 AC: 20350 AN: 52142

Middle Eastern (MID) AF: 0.404 AC: 2056 AN: 5090

European-Non Finnish (NFE) AF: 0.416 AC: 442356 AN: 1063686

Other (OTH) AF: 0.430 AC: 24510 AN: 57026

GnomAD4 genome AF: 0.422 AC: 56364 AN: 133664 Hom.: 17895 Cov.: 24 AF XY: 0.424 AC XY: 27500 AN XY: 64928

African (AFR) AF: 0.373 AC: 11577 AN: 31020

American (AMR) AF: 0.529 AC: 7377 AN: 13936

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1620 AN: 3138

East Asian (EAS) AF: 0.522 AC: 2645 AN: 5064

South Asian (SAS) AF: 0.439 AC: 1712 AN: 3902

European-Finnish (FIN) AF: 0.380 AC: 3732 AN: 9820

Middle Eastern (MID) AF: 0.418 AC: 107 AN: 256

European-Non Finnish (NFE) AF: 0.417 AC: 26588 AN: 63836

Other (OTH) AF: 0.470 AC: 850 AN: 1810

Alfa AF: 0.420 Hom.: 1976

Asia WGS AF: 0.493 AC: 1595 AN: 3236

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		1.5
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: rs414628; hg19: chr1-196801078; COSMIC: COSV57626499; COSMIC: COSV57626499;