chr14-20693649-A-G

Position:

• chr14-20693649-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001097577.3(ANG):​c.85A>G​(p.Arg29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANG NM_001097577.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Significantly decreases binding affinity for RNH1. (size 0) in uniprot entity ANGI_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANG	NM_001097577.3	c.85A>G	p.Arg29Gly	missense_variant	2/2	ENST00000397990.5	NP_001091046.1
RNASE4	NM_002937.5	c.-17-5706A>G		intron_variant		ENST00000555835.3	NP_002928.1
EGILA	NR_174964.1	n.567T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANG	ENST00000397990.5	c.85A>G	p.Arg29Gly	missense_variant	2/2	1	NM_001097577.3	ENSP00000381077	P1
RNASE4	ENST00000555835.3	c.-17-5706A>G		intron_variant		1	NM_002937.5	ENSP00000452245	P1
EGILA	ENST00000554286.1	n.746T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals affected with ANG-related conditions. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 29 of the ANG protein (p.Arg29Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.026	D;D;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.91	P;P;.
Vest4		0.47
MutPred		0.58		Gain of catalytic residue at L34 (P = 0.0013);Gain of catalytic residue at L34 (P = 0.0013);Gain of catalytic residue at L34 (P = 0.0013);
MVP		0.86
MPC		0.38
ClinPred		0.67	D
GERP RS		3.2
Varity_R		0.58
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1886930449; hg19: chr14-21161808;