14-20693894-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001097577.3(ANG):c.330T>G(p.Gly110Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,614,020 control chromosomes in the GnomAD database, including 14,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1367 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13307 hom. )

Consequence

ANG
NM_001097577.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.51

Variant links:

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]

ANG links:

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

RNASE4 links:

ENSG00000259171 (HGNC:):

ENSG00000259171 links:

EGILA (HGNC:54482): (EGFR interacting lncRNA)

EGILA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 14-20693894-T-G is Benign according to our data. Variant chr14-20693894-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 257559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20693894-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANG	NM_001097577.3 link	c.330T>G	p.Gly110Gly	synonymous_variant	Exon 2 of 2	ENST00000397990.5	NP_001091046.1	P03950W0UV28
RNASE4	NM_002937.5 link	c.-17-5461T>G		intron_variant	Intron 1 of 1	ENST00000555835.3	NP_002928.1	P34096Q53XB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANG	ENST00000397990.5 link	c.330T>G	p.Gly110Gly	synonymous_variant	Exon 2 of 2	1	NM_001097577.3	ENSP00000381077.4	P03950
RNASE4	ENST00000555835.3 link	c.-17-5461T>G		intron_variant	Intron 1 of 1	1	NM_002937.5	ENSP00000452245.1	P34096
ENSG00000259171	ENST00000553909.1 link	c.86+244T>G		intron_variant	Intron 2 of 2	2		ENSP00000477037.1	V9GYS4

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20084

AN:

152018

Hom.:

1364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.131

GnomAD3 exomes

AF:

0.137

AC:

34503

AN:

251486

Hom.:

2724

AF XY:

0.138

AC XY:

18709

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.00913

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.131

AC:

190826

AN:

1461884

Hom.:

13307

Cov.:

AF XY:

0.131

AC XY:

95258

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.179

Gnomad4 EAS exome

AF:

0.0104

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.167

Gnomad4 NFE exome

AF:

0.129

Gnomad4 OTH exome

AF:

0.132

GnomAD4 genome

AF:

0.132

AC:

20113

AN:

152136

Hom.:

1367

Cov.:

AF XY:

0.135

AC XY:

10032

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.155

Gnomad4 ASJ

AF:

0.177

Gnomad4 EAS

AF:

0.0114

Gnomad4 SAS

AF:

0.133

Gnomad4 FIN

AF:

0.181

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.126

Hom.:

1279

Bravo

AF:

0.133

Asia WGS

AF:

0.0850

AC:

295

AN:

3478

EpiCase

AF:

0.136

EpiControl

AF:

0.133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15557516, 17462671) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Inborn genetic diseases

Benign:1

May 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Amyotrophic lateral sclerosis type 9

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.55

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over