NM_005754.3:c.668C>G

Variant names:

• chr5-151797355-C-G
• rs1023381854
• NM_005754.3:c.668C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005754.3(G3BP1):​c.668C>G​(p.Ala223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: G3BP1 NM_005754.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12206441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G3BP1	NM_005754.3	c.668C>G	p.Ala223Gly	missense_variant	Exon 7 of 12	ENST00000356245.8	NP_005745.1
G3BP1	NM_198395.2	c.668C>G	p.Ala223Gly	missense_variant	Exon 7 of 12		NP_938405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G3BP1	ENST00000356245.8	c.668C>G	p.Ala223Gly	missense_variant	Exon 7 of 12	1	NM_005754.3	ENSP00000348578.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461674 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.000131 AC: 2 AN: 15268

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668C>G (p.A223G) alteration is located in exon 7 (coding exon 6) of the G3BP1 gene. This alteration results from a C to G substitution at nucleotide position 668, causing the alanine (A) at amino acid position 223 to be replaced by a glycine (G). 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	Benign	0.085
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	2.0	M;M
PhyloP100		0.71
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.092
Sift	Benign	0.18	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.18	B;B
Vest4		0.15
MutPred		0.13		Loss of stability (P = 0.0557);Loss of stability (P = 0.0557);
MVP		0.70
MPC		0.47
ClinPred		0.13	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.15
Mutation Taster		=70/30	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: rs1023381854; hg19: chr5-151176916;