chr14-20693686-A-T

Position:

chr14-20693686-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5BP4_ModerateBS1BS2

The NM_001097577.3(ANG):c.122A>T(p.Lys41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,170 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K41E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00095 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

ANG
NM_001097577.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

Conservation

PhyloP100: 0.204

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 Benign. Variant got -8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-20693685-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 18075.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.24151713).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000946 (144/152276) while in subpopulation SAS AF= 0.00249 (12/4820). AF 95% confidence interval is 0.00144. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ANG	NM_001097577.3 linkuse as main transcript	c.122A>T	p.Lys41Ile	missense_variant	2/2	ENST00000397990.5
RNASE4	NM_002937.5 linkuse as main transcript	c.-17-5669A>T		intron_variant		ENST00000555835.3
EGILA	NR_174964.1 linkuse as main transcript	n.530T>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ANG	ENST00000397990.5 linkuse as main transcript	c.122A>T	p.Lys41Ile	missense_variant	2/2	1	NM_001097577.3	P1
RNASE4	ENST00000555835.3 linkuse as main transcript	c.-17-5669A>T		intron_variant		1	NM_002937.5	P1
EGILA	ENST00000554286.1 linkuse as main transcript	n.709T>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

144

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00118

AC:

298

AN:

251496

Hom.:

AF XY:

0.00123

AC XY:

167

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00177

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00187

AC:

2734

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1369

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00292

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.000946

AC:

144

AN:

152276

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000952

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 9

Pathogenic:1Uncertain:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	Functional analysis suggest that it disrupts protein function under certain laboratory conditions, however these results are inconsistent (Wu et al., 2007; Thiyagarajan et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in healthy controls at the same frequency as in disease populations (van Es et al., 2011); This variant is associated with the following publications: (PMID: 19363631, 28444446, 20577002, 25382069, 22499346, 19444281, 19153377, 22522484, 23447461, 19449021, 17900154, 23047679, 17886298, 23463871, 23155438, 28430856, 22292843, 26255299, 22645277, 29895397, 19488901, 16501576, 22190368, 22384259, 23665167) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ANG: PM5, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 26, 2020

- -

ANG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.090

CADD

Benign

9.3

DANN

Benign

0.78

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.68

.;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0e-7

A;A;A;A;A

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.57

Sift

Benign

0.048

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.13

B;B

Vest4

0.27

MVP

0.78

MPC

0.59

ClinPred

0.071

GERP RS

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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