Genetic Variant ANGEL1:p.Ala521Ser (chr14-76803428-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015305.4(ANGEL1):c.1561G>T(p.Ala521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ANGEL1
NM_015305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21

Variant links:

Genes affected

ANGEL1 (HGNC:19961): (angel homolog 1) Enables eukaryotic initiation factor 4E binding activity and protein domain specific binding activity. Predicted to be involved in RNA phosphodiester bond hydrolysis, exonucleolytic. Located in several cellular components, including cis-Golgi network; endoplasmic reticulum; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANGEL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGEL1	NM_015305.4 link	c.1561G>T	p.Ala521Ser	missense_variant	Exon 7 of 10	ENST00000251089.8	NP_056120.2	Q9UNK9A0A024R6B2
ANGEL1	NM_001370746.1 link	c.1720G>T	p.Ala574Ser	missense_variant	Exon 9 of 12		NP_001357675.1
ANGEL1	NM_001370747.1 link	c.1720G>T	p.Ala574Ser	missense_variant	Exon 9 of 12		NP_001357676.1
ANGEL1	NM_001370748.1 link	c.1561G>T	p.Ala521Ser	missense_variant	Exon 7 of 10		NP_001357677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANGEL1	ENST00000251089.8 link	c.1561G>T	p.Ala521Ser	missense_variant	Exon 7 of 10	1	NM_015305.4	ENSP00000251089.3	Q9UNK9
ANGEL1	ENST00000557179.5 link	c.256G>T	p.Ala86Ser	missense_variant	Exon 2 of 5	2		ENSP00000451534.1	G3V414
ANGEL1	ENST00000555079.1 link	c.-30G>T		5_prime_UTR_variant	Exon 4 of 6	5		ENSP00000452287.1	G3V5C4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251464

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1561G>T (p.A521S) alteration is located in exon 7 (coding exon 7) of the ANGEL1 gene. This alteration results from a G to T substitution at nucleotide position 1561, causing the alanine (A) at amino acid position 521 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.83

N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.011

D;D

Sift4G

Benign

0.14

T;D

Polyphen

1.0

D;.

Vest4

0.65

MutPred

0.50

Gain of catalytic residue at I520 (P = 0.0271);.;

MVP

0.88

MPC

0.58

ClinPred

0.85

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.66

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

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