5-151791058-C-T

Variant names:

• chr5-151791058-C-T
• NM_005754.3:c.347C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005754.3(G3BP1):​c.347C>T​(p.Pro116Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: G3BP1 NM_005754.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• Publications: 0 publications found

Genes affected

G3BP1 (HGNC:30292): (G3BP stress granule assembly factor 1) This gene encodes one of the DNA-unwinding enzymes which prefers partially unwound 3'-tailed substrates and can also unwind partial RNA/DNA and RNA/RNA duplexes in an ATP-dependent fashion. This enzyme is a member of the heterogeneous nuclear RNA-binding proteins and is also an element of the Ras signal transduction pathway. It binds specifically to the Ras-GTPase-activating protein by associating with its SH3 domain. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G3BP1	NM_005754.3	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 12	ENST00000356245.8	NP_005745.1
G3BP1	NM_198395.2	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 12		NP_938405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G3BP1	ENST00000356245.8	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 12	1	NM_005754.3	ENSP00000348578.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 29, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;D;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.2	.;M;M;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.13	T;T;T;T
Sift4G	Uncertain	0.0040	D;T;T;D
Polyphen		0.35	.;B;B;.
Vest4		0.90, 0.92
MutPred		0.72		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;
MVP		0.87
MPC		0.49
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		0.018	Neutral
Varity_R		0.53
gMVP		0.50
Mutation Taster		=155/145	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

hg19: chr5-151170619;