chr4-89248453-C-G

Position:

• chr4-89248453-C-G

Variant summary

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

The NM_198281.3(GPRIN3):​c.1658G>C​(p.Gly553Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000082 (0 hom.)
• Consequence: GPRIN3 NM_198281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161

Genes affected

GPRIN3 (HGNC:27733): (GPRIN family member 3) Predicted to be involved in neuron projection development. Predicted to be active in plasma membrane. [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=0.0626781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPRIN3	NM_198281.3	c.1658G>C	p.Gly553Ala	missense_variant	2/2	ENST00000609438.2	NP_938022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPRIN3	ENST00000609438.2	c.1658G>C	p.Gly553Ala	missense_variant	2/2	2	NM_198281.3	ENSP00000476603.1
GPRIN3	ENST00000333209.4	c.1658G>C	p.Gly553Ala	missense_variant	1/1	6		ENSP00000328672.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461064 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 726844

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 28, 2024

The c.1658G>C (p.G553A) alteration is located in exon 2 (coding exon 1) of the GPRIN3 gene. This alteration results from a G to C substitution at nucleotide position 1658, causing the glycine (G) at amino acid position 553 to be replaced by an alanine (A). 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	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.14
DEOGEN2	Benign	0.0027	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.63	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.059
Sift	Benign	0.48	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.29	B;B
Vest4		0.065
MutPred		0.091		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.030
MPC		0.049
ClinPred		0.14	T
GERP RS		-0.99
Varity_R		0.041
gMVP		0.079

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

LitVar

Other links and lift over

dbSNP: rs1364728011; hg19: chr4-90169604;