Genetic Variant NM_015305.4:c.1603A>G (chr14-76803386-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015305.4(ANGEL1):c.1603A>G(p.Thr535Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (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: 7.31

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015305.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGEL1	NM_015305.4	MANE Select	c.1603A>G	p.Thr535Ala	missense	Exon 7 of 10	NP_056120.2	Q9UNK9
ANGEL1	NM_001370746.1		c.1762A>G	p.Thr588Ala	missense	Exon 9 of 12	NP_001357675.1
ANGEL1	NM_001370747.1		c.1762A>G	p.Thr588Ala	missense	Exon 9 of 12	NP_001357676.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGEL1	ENST00000251089.8	TSL:1 MANE Select	c.1603A>G	p.Thr535Ala	missense	Exon 7 of 10	ENSP00000251089.3	Q9UNK9
ANGEL1	ENST00000851327.1		c.1762A>G	p.Thr588Ala	missense	Exon 9 of 12	ENSP00000521386.1
ANGEL1	ENST00000557497.2	TSL:2	c.1642A>G	p.Thr548Ala	missense	Exon 8 of 11	ENSP00000498076.2	A0A3B3IU54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251362

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

-0.095

MutationAssessor

Uncertain

2.0

PhyloP100

7.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.58

Sift

Benign

0.041

Sift4G

Uncertain

0.042

Polyphen

0.26

Vest4

0.76

MutPred

0.41

Gain of catalytic residue at V534 (P = 0)

MVP

0.79

MPC

0.61

ClinPred

0.69

GERP RS

5.5

Varity_R

0.17

gMVP

0.75

Mutation Taster

=47/53

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over