chr14-20693567-G-A

Position:

chr14-20693567-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.54

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:

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

EGILA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ANG	NM_001097577.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/2	ENST00000397990.5	NP_001091046.1
RNASE4	NM_002937.5 linkuse as main transcript	c.-17-5788G>A		intron_variant		ENST00000555835.3	NP_002928.1
EGILA	NR_174964.1 linkuse as main transcript	n.649C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ANG	ENST00000397990.5 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/2	1	NM_001097577.3	ENSP00000381077	P1
RNASE4	ENST00000555835.3 linkuse as main transcript	c.-17-5788G>A		intron_variant		1	NM_002937.5	ENSP00000452245	P1
EGILA	ENST00000554286.1 linkuse as main transcript	n.828C>T		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

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:

AN:

250014

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

135258

show subpopulations

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.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

726346

show subpopulations

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74362

show subpopulations

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.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -
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) -

ANG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

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

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

T;T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.10

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

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

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