14-20684445-C-A

Position:

• chr14-20684445-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000336811.10(ANG):​c.-332C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,262 control chromosomes in the GnomAD database, including 918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (918 hom., cov: 32)
  • Exomes 𝑓: 0.070 (0 hom.)
• Consequence: ANG ENST00000336811.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.814

Genes affected

ANG (HGNC:483): (angiogenin) The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 14-20684445-C-A is Benign according to our data. Variant chr14-20684445-C-A is described in ClinVar as [Benign]. Clinvar id is 312768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANG	NM_001145.4	c.-332C>A		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANG	ENST00000336811.10	c.-332C>A		5_prime_UTR_variant	1/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16492 AN: 152030 Hom.: 916 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0702 AC: 8 AN: 114 Hom.: 0 Cov.: 0 AF XY: 0.0732 AC XY: 6 AN XY: 82

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0800

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.109 AC: 16511 AN: 152148 Hom.: 918 Cov.: 32 AF XY: 0.107 AC XY: 7947 AN XY: 74408

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0244

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.107

Alfa AF: 0.117 Hom.: 154

Bravo AF: 0.113

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.2
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs28589501; hg19: chr14-21152604;