14-20693894-T-G

Variant names:

• chr14-20693894-T-G
• rs11701
• NM_001097577.3:c.330T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.51
• Publications: 48 publications found

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]

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]

ENSG00000259171 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 257559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097577.3. 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
	ANG	NM_001097577.3	MANE Select	c.330T>G	p.Gly110Gly	synonymous	Exon 2 of 2	NP_001091046.1
	RNASE4	NM_002937.5	MANE Select	c.-17-5461T>G		intron	N/A	NP_002928.1
	ANG	NM_001145.4		c.330T>G	p.Gly110Gly	synonymous	Exon 2 of 2	NP_001136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	ENST00000397990.5	TSL:1 MANE Select	c.330T>G	p.Gly110Gly	synonymous	Exon 2 of 2	ENSP00000381077.4
	ANG	ENST00000336811.10	TSL:1	c.330T>G	p.Gly110Gly	synonymous	Exon 2 of 2	ENSP00000336762.6
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-17-5461T>G		intron	N/A	ENSP00000452245.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20084 AN: 152018 Hom.: 1364 Cov.: 32

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

GnomAD2 exomes AF: 0.137 AC: 34503 AN: 251486 AF XY: 0.138

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 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.: 32 AF XY: 0.131 AC XY: 95258 AN XY: 727242

African (AFR) AF: 0.123 AC: 4114 AN: 33478

American (AMR) AF: 0.176 AC: 7893 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4688 AN: 26136

East Asian (EAS) AF: 0.0104 AC: 413 AN: 39700

South Asian (SAS) AF: 0.143 AC: 12315 AN: 86258

European-Finnish (FIN) AF: 0.167 AC: 8896 AN: 53420

Middle Eastern (MID) AF: 0.206 AC: 1189 AN: 5768

European-Non Finnish (NFE) AF: 0.129 AC: 143325 AN: 1112004

Other (OTH) AF: 0.132 AC: 7993 AN: 60396

GnomAD4 genome AF: 0.132 AC: 20113 AN: 152136 Hom.: 1367 Cov.: 32 AF XY: 0.135 AC XY: 10032 AN XY: 74374

African (AFR) AF: 0.126 AC: 5238 AN: 41518

American (AMR) AF: 0.155 AC: 2367 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3470

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5182

South Asian (SAS) AF: 0.133 AC: 640 AN: 4810

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10568

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8746 AN: 67978

Other (OTH) AF: 0.130 AC: 275 AN: 2114

Alfa AF: 0.127 Hom.: 3124

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

Submissions by phenotype

not specified Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:3

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

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)

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.55
DANN	Benign	0.48
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11701; hg19: chr14-21162053; COSMIC: COSV59012958;