Genetic Variant GSPT1:p.Glu164Lys (chr16-11896732-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002094.4(GSPT1):c.490G>A(p.Glu164Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,603,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

GSPT1
NM_002094.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

GSPT1 (HGNC:4621): (G1 to S phase transition 1) Enables translation release factor activity. Involved in regulation of translational termination. Acts upstream of or within protein methylation. Predicted to be located in cytosol. Predicted to be part of translation release factor complex. [provided by Alliance of Genome Resources, Apr 2022]

GSPT1 links:

RSL1D1-DT (HGNC:55337): (RSL1D1 divergent transcript)

RSL1D1-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2829756).

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSPT1	NM_002094.4 link	c.490G>A	p.Glu164Lys	missense_variant	Exon 4 of 15	ENST00000434724.7	NP_002085.3	Q7KZX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSPT1	ENST00000434724.7 link	c.490G>A	p.Glu164Lys	missense_variant	Exon 4 of 15	1	NM_002094.4	ENSP00000398131.2		P15170-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000867

AC:

AN:

230676

Hom.:

AF XY:

0.00

AC XY:

AN XY:

124522

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1451124

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

720732

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000361

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.490G>A (p.E164K) alteration is located in exon 4 (coding exon 4) of the GSPT1 gene. This alteration results from a G to A substitution at nucleotide position 490, causing the glutamic acid (E) at amino acid position 164 to be replaced by a lysine (K). 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

0.12

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

.;.;T;T;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.28

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

.;.;L;L;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.55

N;N;N;N;N;D

REVEL

Benign

0.19

Sift

Uncertain

0.029

D;T;D;D;D;D

Sift4G

Benign

0.55

T;T;T;T;.;D

Polyphen

0.034

.;.;B;B;.;.

Vest4

0.61

MutPred

0.15

.;.;Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);.;.;

MVP

0.52

MPC

0.68

ClinPred

0.76

GERP RS

5.3

Varity_R

0.18

gMVP

0.56

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