chr16-11896591-C-G

Variant names:

• chr16-11896591-C-G
• rs1211484044
• NM_002094.4:c.631G>C

Variant summary

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

The NM_002094.4(GSPT1):​c.631G>C​(p.Glu211Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,528 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: 6.9e-7 (0 hom.)
• Consequence: GSPT1 NM_002094.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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]

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

ACMG classification

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
GSPT1	NM_002094.4	c.631G>C	p.Glu211Gln	missense_variant	Exon 4 of 15	ENST00000434724.7	NP_002085.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSPT1	ENST00000434724.7	c.631G>C	p.Glu211Gln	missense_variant	Exon 4 of 15	1	NM_002094.4	ENSP00000398131.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237546 Hom.: 0 AF XY: 0.00000778 AC XY: 1 AN XY: 128492

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000576

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453528 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.631G>C (p.E211Q) alteration is located in exon 4 (coding exon 4) of the GSPT1 gene. This alteration results from a G to C substitution at nucleotide position 631, causing the glutamic acid (E) at amino acid position 211 to be replaced by a glutamine (Q). 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	0.57
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	.;.;L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.024	D;D;T;T;D
Sift4G	Uncertain	0.021	D;D;T;T;.
Polyphen		1.0	.;.;D;D;.
Vest4		0.62
MutPred		0.27		.;.;Loss of ubiquitination at K71 (P = 0.0394);Loss of ubiquitination at K71 (P = 0.0394);.;
MVP		0.61
MPC		0.87
ClinPred		0.88	D
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.54
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1211484044; hg19: chr16-11990448;