chr5-151790995-T-C

Variant names:

• chr5-151790995-T-C
• NM_005754.3:c.284T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005754.3(G3BP1):​c.284T>C​(p.Met95Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: G3BP1 NM_005754.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• 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 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
G3BP1	NM_005754.3	c.284T>C	p.Met95Thr	missense_variant	Exon 4 of 12	ENST00000356245.8	NP_005745.1
G3BP1	NM_198395.2	c.284T>C	p.Met95Thr	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.284T>C	p.Met95Thr	missense_variant	Exon 4 of 12	1	NM_005754.3	ENSP00000348578.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461378 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.284T>C (p.M95T) alteration is located in exon 4 (coding exon 3) of the G3BP1 gene. This alteration results from a T to C substitution at nucleotide position 284, causing the methionine (M) at amino acid position 95 to be replaced by a threonine (T). 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	0.70
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.0089	.;T;T;T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;T;.;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.23	.;.;N;N;.;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.75	N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.67	T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Polyphen		0.016	.;.;B;B;.;.
Vest4		0.89
MutPred		0.57		Loss of catalytic residue at V91 (P = 0.041);Loss of catalytic residue at V91 (P = 0.041);Loss of catalytic residue at V91 (P = 0.041);Loss of catalytic residue at V91 (P = 0.041);.;Loss of catalytic residue at V91 (P = 0.041);
MVP		0.91
MPC		0.53
ClinPred		0.82	D
GERP RS		4.7
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.43
Mutation Taster		=193/107	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: chr5-151170556;