14-20693567-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001097577.3(ANG):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000163 in 1,612,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ANG NM_001097577.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.54

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.

• PVS1: Start lost variant, no new inframe start found.
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANG	NM_001097577.3	c.3G>A	p.Met1?	start_lost	2/2	ENST00000397990.5
RNASE4	NM_002937.5	c.-17-5788G>A		intron_variant		ENST00000555835.3
EGILA	NR_174964.1	n.649C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANG	ENST00000397990.5	c.3G>A	p.Met1?	start_lost	2/2	1	NM_001097577.3	P1
RNASE4	ENST00000555835.3	c.-17-5788G>A		intron_variant		1	NM_002937.5	P1
EGILA	ENST00000554286.1	n.828C>T		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000216 AC: 54 AN: 250014 Hom.: 0 AF XY: 0.000274 AC XY: 37 AN XY: 135258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1460014 Hom.: 0 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 726346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2020	Previously identified in individuals with PD, ALS and/or FTLD; one of these individuals who was heterozygous for c.3G>T, which also leads to an M1? varinat, also harbored a pathogenic variant in the SOD1 gene (van Es, et al., 2011; Conforti, et al., 2008; Gellera et al., 2008; Tripolszki et al., 2019); Variant is located within the signal peptide and affecting the start codon, which may influence the correct translation of the protein; ; however, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. .; This variant is associated with the following publications: (PMID: 22190368, 17703939, 28444446, 18087731, 31025543) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

ANG-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The ANG c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). This variant, which is located in the signal peptide region and has been previously described in the literature as Met-24Ile, has been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), Parkinson disease/parkinsonism, or frontotemporal dementia (Conforti et al. 2008. PubMed ID: 17703939; Gellera et al. 2008. PubMed ID: 18087731; van Es et al. 2011. PubMed ID: 22190368; Marjanović et al. 2017. PubMed ID: 28444446; Ungaro et al. 2020. PubMed ID: 32951934). To our knowledge, functional studies have not been performed to better understand the biological relevance of this variant. This variant is reported in 0.097% of alleles in individuals of Ashkenazi Jewish descent, and 0.022% overall in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Amyotrophic lateral sclerosis type 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Amyotrophic lateral sclerosis type 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Oct 21, 2022

ACMG criteria used to clasify this variant: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.033	T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	1.0	D;D;D;N;N
PROVEAN	Benign	-1.7	N;N;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.016	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.89	P;P;.
Vest4		0.89
MutPred		0.94		Gain of catalytic residue at V2 (P = 0.0012);Gain of catalytic residue at V2 (P = 0.0012);Gain of catalytic residue at V2 (P = 0.0012);
MVP		0.88
ClinPred		0.073	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.50
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs201068740; hg19: chr14-21161726;