chr5-151790394-A-G

Variant names:

• chr5-151790394-A-G
• NM_005754.3:c.167A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005754.3(G3BP1):​c.167A>G​(p.Tyr56Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000422 in 1,422,252 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: 0.0000042 (0 hom.)
• Consequence: G3BP1 NM_005754.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65
• 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_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G3BP1	NM_005754.3	c.167A>G	p.Tyr56Cys	missense_variant	Exon 3 of 12	ENST00000356245.8	NP_005745.1
G3BP1	NM_198395.2	c.167A>G	p.Tyr56Cys	missense_variant	Exon 3 of 12		NP_938405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G3BP1	ENST00000356245.8	c.167A>G	p.Tyr56Cys	missense_variant	Exon 3 of 12	1	NM_005754.3	ENSP00000348578.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1422252 Hom.: 0 Cov.: 24 AF XY: 0.00000848 AC XY: 6 AN XY: 707884

African (AFR) AF: 0.00 AC: 0 AN: 31502

American (AMR) AF: 0.00 AC: 0 AN: 40266

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38106

South Asian (SAS) AF: 0.00 AC: 0 AN: 80508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1088630

Other (OTH) AF: 0.00 AC: 0 AN: 58758

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 18, 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	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;T;D;D;.;T
Eigen	Benign	0.021
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	.;.;M;M;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.099	T;T;D;D;D;T
Sift4G	Uncertain	0.035	D;T;T;T;T;D
Polyphen		0.10	.;.;B;B;.;.
Vest4		0.81, 0.80
MutPred		0.48		Loss of phosphorylation at Y56 (P = 0.0283);Loss of phosphorylation at Y56 (P = 0.0283);Loss of phosphorylation at Y56 (P = 0.0283);Loss of phosphorylation at Y56 (P = 0.0283);.;Loss of phosphorylation at Y56 (P = 0.0283);
MVP		0.72
MPC		1.3
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.51
Mutation Taster		=281/19	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: chr5-151169955;