NM_002113.3:c.253+66G>A

Variant names:

• chr1-196825737-G-A
• rs372075
• NM_002113.3:c.253+66G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002113.3(CFHR1):​c.253+66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,386,212 control chromosomes in the GnomAD database, including 40,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (5403 hom., cov: 24)
  • Exomes 𝑓: 0.14 (35131 hom.)
• Consequence: CFHR1 NM_002113.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-196825737-G-A is Benign according to our data. Variant chr1-196825737-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

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.253+66G>A		intron	N/A	NP_002104.2
	CFHR1	NM_001379306.1		c.202+66G>A		intron	N/A	NP_001366235.1
	CFHR1	NM_001379307.1		c.91+66G>A		intron	N/A	NP_001366236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR1	ENST00000320493.10	TSL:1 MANE Select	c.253+66G>A		intron	N/A	ENSP00000314299.5
	CFHR1	ENST00000468079.1	TSL:2	n.299G>A		non_coding_transcript_exon	Exon 2 of 2
	CFHR1	ENST00000699454.1		c.91+66G>A		intron	N/A	ENSP00000514391.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 21459 AN: 133986 Hom.: 5399 Cov.: 24

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0295

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0714

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.273

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.143 AC: 179523 AN: 1252110 Hom.: 35131 Cov.: 22 AF XY: 0.142 AC XY: 88774 AN XY: 626204

African (AFR) AF: 0.242 AC: 5453 AN: 22538

American (AMR) AF: 0.116 AC: 4904 AN: 42382

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3952 AN: 22714

East Asian (EAS) AF: 0.109 AC: 4209 AN: 38640

South Asian (SAS) AF: 0.0803 AC: 5718 AN: 71170

European-Finnish (FIN) AF: 0.0777 AC: 3935 AN: 50654

Middle Eastern (MID) AF: 0.199 AC: 938 AN: 4712

European-Non Finnish (NFE) AF: 0.151 AC: 142582 AN: 947242

Other (OTH) AF: 0.150 AC: 7832 AN: 52058

GnomAD4 genome AF: 0.160 AC: 21466 AN: 134102 Hom.: 5403 Cov.: 24 AF XY: 0.155 AC XY: 10106 AN XY: 65142

African (AFR) AF: 0.234 AC: 7283 AN: 31146

American (AMR) AF: 0.151 AC: 2100 AN: 13934

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 519 AN: 3134

East Asian (EAS) AF: 0.111 AC: 563 AN: 5060

South Asian (SAS) AF: 0.0714 AC: 277 AN: 3878

European-Finnish (FIN) AF: 0.0696 AC: 694 AN: 9978

Middle Eastern (MID) AF: 0.274 AC: 68 AN: 248

European-Non Finnish (NFE) AF: 0.151 AC: 9638 AN: 64030

Other (OTH) AF: 0.164 AC: 298 AN: 1814

Alfa AF: 0.149 Hom.: 593

Asia WGS AF: 0.0820 AC: 268 AN: 3244

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 09, 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.39
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372075; hg19: chr1-196794867;