chr1-196774797-A-C

Variant names:

• chr1-196774797-A-C
• rs385390
• ENST00000696032.1:c.3581-4365A>C

Variant summary

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

The ENST00000696032.1(ENSG00000289697):​c.3581-4365A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,144,398 control chromosomes in the GnomAD database, including 59,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (10829 hom., cov: 24)
  • Exomes 𝑓: 0.23 (48181 hom.)
• Consequence: ENSG00000289697 ENST00000696032.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.324
• Publications: 5 publications found

Genes affected

ENSG00000289697 (HGNC:):

CFHR3 (HGNC:16980): (complement factor H related 3) The protein encoded by this gene is a secreted protein, which belongs to the complement factor H-related protein family. It binds to heparin, and may be involved in complement regulation. Mutations in this gene are associated with decreased risk of age-related macular degeneration, and with an increased risk of atypical hemolytic-uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

CFHR3 Gene-Disease associations (from GenCC):

• hemolytic uremic syndrome, atypical, susceptibility to, 1

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-196774797-A-C is Benign according to our data. Variant chr1-196774797-A-C is described in ClinVar as Benign. ClinVar VariationId is 1233740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR3	NM_021023.6	c.-90A>C		upstream_gene_variant		ENST00000367425.9	NP_066303.2
CFHR3	NM_001166624.2	c.-90A>C		upstream_gene_variant			NP_001160096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289697	ENST00000696032.1	c.3581-4365A>C		intron_variant	Intron 22 of 26			ENSP00000512341.1
CFHR3	ENST00000367425.9	c.-90A>C		upstream_gene_variant		1	NM_021023.6	ENSP00000356395.5

Frequencies

GnomAD3 genomes AF: 0.280 AC: 37959 AN: 135512 Hom.: 10813 Cov.: 24

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.233 AC: 235332 AN: 1008760 Hom.: 48181 Cov.: 14 AF XY: 0.230 AC XY: 118325 AN XY: 513554

African (AFR) AF: 0.426 AC: 7801 AN: 18302

American (AMR) AF: 0.409 AC: 16469 AN: 40252

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 4177 AN: 20510

East Asian (EAS) AF: 0.505 AC: 18694 AN: 37046

South Asian (SAS) AF: 0.208 AC: 13593 AN: 65364

European-Finnish (FIN) AF: 0.160 AC: 7760 AN: 48604

Middle Eastern (MID) AF: 0.236 AC: 952 AN: 4028

European-Non Finnish (NFE) AF: 0.212 AC: 155275 AN: 731428

Other (OTH) AF: 0.245 AC: 10611 AN: 43226

GnomAD4 genome AF: 0.280 AC: 37994 AN: 135638 Hom.: 10829 Cov.: 24 AF XY: 0.279 AC XY: 18444 AN XY: 66056

African (AFR) AF: 0.419 AC: 13568 AN: 32370

American (AMR) AF: 0.310 AC: 4318 AN: 13936

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 619 AN: 3152

East Asian (EAS) AF: 0.506 AC: 2559 AN: 5062

South Asian (SAS) AF: 0.217 AC: 851 AN: 3918

European-Finnish (FIN) AF: 0.162 AC: 1639 AN: 10094

Middle Eastern (MID) AF: 0.297 AC: 76 AN: 256

European-Non Finnish (NFE) AF: 0.212 AC: 13617 AN: 64142

Other (OTH) AF: 0.273 AC: 500 AN: 1834

Alfa AF: 0.259 Hom.: 1112

Asia WGS AF: 0.301 AC: 979 AN: 3248

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.9
DANN	Benign	0.30
PhyloP100		-0.32
PromoterAI		-0.013	Neutral
Mutation Taster		=300/0	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: rs385390; hg19: chr1-196743927; COSMIC: COSV66403242; COSMIC: COSV66403242;