4-75648729-C-T

Position:

• chr4-75648729-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203505.3(G3BP2):​c.838G>A​(p.Ala280Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: G3BP2 NM_203505.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632

Genes affected

G3BP2 (HGNC:30291): (G3BP stress granule assembly factor 2) Enables RNA binding activity. Involved in positive regulation of stress granule assembly and protein homooligomerization. Located in cytoplasmic stress granule and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035157174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G3BP2	NM_203505.3	c.838G>A	p.Ala280Thr	missense_variant	9/12	ENST00000359707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G3BP2	ENST00000359707.9	c.838G>A	p.Ala280Thr	missense_variant	9/12	1	NM_203505.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448992 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.838G>A (p.A280T) alteration is located in exon 9 (coding exon 8) of the G3BP2 gene. This alteration results from a G to A substitution at nucleotide position 838, causing the alanine (A) at amino acid position 280 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	Benign	0.060
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.084	T;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.14	N;N;.
MutationTaster	Benign	0.51	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.020	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.089
MutPred		0.23		Loss of MoRF binding (P = 0.1208);Loss of MoRF binding (P = 0.1208);.;
MVP		0.23
MPC		0.094
ClinPred		0.26	T
GERP RS		2.9
Varity_R		0.022
gMVP		0.12

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-76573913;