19-12748013-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004317.4(GET3):​c.956C>T​(p.Pro319Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000206 in 1,459,338 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

GET3
NM_004317.4 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.92
Variant links:
Genes affected
GET3 (HGNC:752): (guided entry of tail-anchored proteins factor 3, ATPase) This gene represents the human homolog of the bacterial arsA gene, encoding the arsenite-stimulated ATPase component of the arsenite transporter responsible for resistance to arsenicals. This protein is also a central component of a transmembrane domain (TMD) recognition complex (TRC) that is involved in the post-translational delivery of tail-anchored (TA) proteins from the cytosol to the endoplasmic reticulum (ER). It recognizes and selectively binds the TMD of TA proteins in the cytosol, and delivers them to the ER for insertion. [provided by RefSeq, Oct 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GET3NM_004317.4 linkc.956C>T p.Pro319Leu missense_variant Exon 7 of 7 ENST00000357332.8 NP_004308.2 O43681
GET3NM_001371488.1 linkc.956C>T p.Pro319Leu missense_variant Exon 8 of 8 NP_001358417.1
GET3NM_001371489.1 linkc.956C>T p.Pro319Leu missense_variant Exon 8 of 8 NP_001358418.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GET3ENST00000357332.8 linkc.956C>T p.Pro319Leu missense_variant Exon 7 of 7 1 NM_004317.4 ENSP00000349887.3 O43681
GET3ENST00000591090.5 linkc.956C>T p.Pro319Leu missense_variant Exon 8 of 8 5 ENSP00000466379.1 O43681

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000360
AC:
9
AN:
250284
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135244
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000872
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000442
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1459338
Hom.:
0
Cov.:
31
AF XY:
0.0000207
AC XY:
15
AN XY:
725680
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000673
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000991
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 13, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.956C>T (p.P319L) alteration is located in exon 7 (coding exon 7) of the ASNA1 gene. This alteration results from a C to T substitution at nucleotide position 956, causing the proline (P) at amino acid position 319 to be replaced by a leucine (L). 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
Pathogenic
0.97
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;D;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.90
D;D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
3.3
M;M;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-9.2
.;D;.
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.81
MVP
0.74
MPC
1.7
ClinPred
1.0
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.90

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.

Other links and lift over

dbSNP: rs774637174; hg19: chr19-12858827; API