14-20693734-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001097577.3(ANG):​c.170G>T​(p.Arg57Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Failed GnomAD Quality Control

Consequence

ANG
NM_001097577.3 missense

Scores

6
6
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55
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]
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]
EGILA (HGNC:54482): (EGFR interacting lncRNA)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANGNM_001097577.3 linkc.170G>T p.Arg57Leu missense_variant Exon 2 of 2 ENST00000397990.5 NP_001091046.1 P03950W0UV28
RNASE4NM_002937.5 linkc.-17-5621G>T intron_variant Intron 1 of 1 ENST00000555835.3 NP_002928.1 P34096Q53XB4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANGENST00000397990.5 linkc.170G>T p.Arg57Leu missense_variant Exon 2 of 2 1 NM_001097577.3 ENSP00000381077.4 P03950
RNASE4ENST00000555835.3 linkc.-17-5621G>T intron_variant Intron 1 of 1 1 NM_002937.5 ENSP00000452245.1 P34096
ENSG00000259171ENST00000553909.1 linkc.86+84G>T intron_variant Intron 2 of 2 2 ENSP00000477037.1 V9GYS4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000657
AC:
1
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.0062
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.69
.;T
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.2
M;M
PrimateAI
Benign
0.37
T
PROVEAN
Pathogenic
-6.9
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.014
D;D
Sift4G
Uncertain
0.059
T;T
Polyphen
0.72
P;P
Vest4
0.58
MutPred
0.63
Gain of catalytic residue at P62 (P = 8e-04);Gain of catalytic residue at P62 (P = 8e-04);
MVP
0.97
MPC
0.55
ClinPred
0.97
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.78
gMVP
0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21161893; API