rs191734103

Variant names:

• chr1-196774952-A-G
• rs191734103
• NM_021023.6:c.58+8A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021023.6(CFHR3):​c.58+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,520,532 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 25)
  • Exomes 𝑓: 0.000016 (4 hom.)
• Consequence: CFHR3 NM_021023.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001400
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.677

Genes affected

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]

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 1-196774952-A-G is Benign according to our data. Variant chr1-196774952-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 782688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR3	NM_021023.6	c.58+8A>G		splice_region_variant, intron_variant	Intron 1 of 5	ENST00000367425.9	NP_066303.2
CFHR3	NM_001166624.2	c.58+8A>G		splice_region_variant, intron_variant	Intron 1 of 4		NP_001160096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR3	ENST00000367425.9	c.58+8A>G		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_021023.6	ENSP00000356395.5
ENSG00000289697	ENST00000696032.1	c.3581-4210A>G		intron_variant	Intron 22 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 185 AN: 136896 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.000273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000310

Gnomad OTH AF: 0.00217

GnomAD2 exomes AF: 0.0000126 AC: 3 AN: 238120 AF XY: 0.0000156

Gnomad AFR exome AF: 0.0000733

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1383514 Hom.: 4 Cov.: 29 AF XY: 0.0000175 AC XY: 12 AN XY: 687640

African (AFR) AF: 0.00 AC: 0 AN: 27416

American (AMR) AF: 0.00 AC: 0 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24242

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.00 AC: 0 AN: 76388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5072

European-Non Finnish (NFE) AF: 0.0000161 AC: 17 AN: 1058184

Other (OTH) AF: 0.0000878 AC: 5 AN: 56918

GnomAD4 genome AF: 0.00134 AC: 184 AN: 137018 Hom.: 2 Cov.: 25 AF XY: 0.00148 AC XY: 99 AN XY: 66724

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

African (AFR) AF: 0.000272 AC: 9 AN: 33080

American (AMR) AF: 0.0120 AC: 168 AN: 13948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3188

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 3966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000310 AC: 2 AN: 64498

Other (OTH) AF: 0.00215 AC: 4 AN: 1860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00135 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.4
DANN	Benign	0.46
PromoterAI		0.0038
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs191734103; hg19: chr1-196744082; COSMIC: COSV66402498;