chr16-11896676-C-G

Variant names:

• chr16-11896676-C-G
• rs369548013
• NM_002094.4:c.546G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002094.4(GSPT1):​c.546G>C​(p.Glu182Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,608,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E182G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: GSPT1 NM_002094.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.386
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09253949).
• BS2: High AC in GnomAd4 at 18 AD gene.

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.546G>C	p.Glu182Asp	missense	Exon 4 of 15	NP_002085.3	P15170-3
	GSPT1	NM_001130006.2		c.543G>C	p.Glu181Asp	missense	Exon 4 of 15	NP_001123478.2	P15170-2
	GSPT1	NM_001130007.2		c.132G>C	p.Glu44Asp	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.546G>C	p.Glu182Asp	missense	Exon 4 of 15	ENSP00000398131.2	P15170-3
	GSPT1	ENST00000439887.6	TSL:1	c.543G>C	p.Glu181Asp	missense	Exon 4 of 15	ENSP00000408399.2	P15170-2
	GSPT1	ENST00000420576.6	TSL:1	c.132G>C	p.Glu44Asp	missense	Exon 4 of 15	ENSP00000399539.2	P15170-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000134 AC: 32 AN: 239364 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000900

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000133 AC: 193 AN: 1456084 Hom.: 1 Cov.: 30 AF XY: 0.000152 AC XY: 110 AN XY: 723694

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.000251 AC: 11 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000342 AC: 29 AN: 84896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5762

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1109210

Other (OTH) AF: 0.000233 AC: 14 AN: 60208

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.39
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.047
Sift	Benign	0.13	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.14		Gain of sheet (P = 0.0827)
MVP		0.61
MPC		0.32
ClinPred		0.031	T
GERP RS		2.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Varity_R		0.076
gMVP		0.29
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs369548013; hg19: chr16-11990533;