5-151791054-G-C

Variant names:

• chr5-151791054-G-C
• NM_005754.3:c.343G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005754.3(G3BP1):​c.343G>C​(p.Ala115Pro) 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. 13/22 in silico tools predict a damaging 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: 9.77
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G3BP1	NM_005754.3	c.343G>C	p.Ala115Pro	missense_variant	Exon 4 of 12	ENST00000356245.8	NP_005745.1
G3BP1	NM_198395.2	c.343G>C	p.Ala115Pro	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.343G>C	p.Ala115Pro	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 specified Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343G>C (p.A115P) alteration is located in exon 4 (coding exon 3) of the G3BP1 gene. This alteration results from a G to C substitution at nucleotide position 343, causing the alanine (A) at amino acid position 115 to be replaced by a proline (P). 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	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.7	.;H;H;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;T
Polyphen		1.0	.;D;D;.
Vest4		0.92, 0.91
MutPred		0.80		Gain of catalytic residue at A115 (P = 0.0688);Gain of catalytic residue at A115 (P = 0.0688);Gain of catalytic residue at A115 (P = 0.0688);.;
MVP		0.89
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.012	Neutral
Varity_R		0.96
gMVP		0.81
Mutation Taster		=196/104	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: chr5-151170615;