16-11896591-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002094.4(GSPT1):​c.631G>A​(p.Glu211Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E211Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSPT1 NM_002094.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002094.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSPT1	NM_002094.4	MANE Select	c.631G>A	p.Glu211Lys	missense	Exon 4 of 15	NP_002085.3	P15170-3
	GSPT1	NM_001130006.2		c.628G>A	p.Glu210Lys	missense	Exon 4 of 15	NP_001123478.2	P15170-2
	GSPT1	NM_001130007.2		c.217G>A	p.Glu73Lys	missense	Exon 4 of 15	NP_001123479.1	P15170-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSPT1	ENST00000434724.7	TSL:1 MANE Select	c.631G>A	p.Glu211Lys	missense	Exon 4 of 15	ENSP00000398131.2	P15170-3
	GSPT1	ENST00000439887.6	TSL:1	c.628G>A	p.Glu210Lys	missense	Exon 4 of 15	ENSP00000408399.2	P15170-2
	GSPT1	ENST00000420576.6	TSL:1	c.217G>A	p.Glu73Lys	missense	Exon 4 of 15	ENSP00000399539.2	P15170-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453528 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722088

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 84454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107736

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.37		Gain of methylation at E73 (P = 0.0023)
MVP		0.72
MPC		0.67
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.80
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1211484044; hg19: chr16-11990448;