4-98391984-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100427.2(RAP1GDS1):c.541G>A(p.Val181Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAP1GDS1 NM_001100427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

Genes affected

RAP1GDS1 (HGNC:9859): (Rap1 GTPase-GDP dissociation stimulator 1) The smg GDP dissociation stimulator (smgGDS) protein is a stimulatory GDP/GTP exchange protein with GTPase activity (Riess et al., 1993 [PubMed 8262526]).[supplied by OMIM, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3271064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1GDS1	NM_001100427.2	c.541G>A	p.Val181Ile	missense_variant	6/15	ENST00000408927.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1GDS1	ENST00000408927.8	c.541G>A	p.Val181Ile	missense_variant	6/15	2	NM_001100427.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456610 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 33

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

Feb 05, 2024

The c.544G>A (p.V182I) alteration is located in exon 6 (coding exon 6) of the RAP1GDS1 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the valine (V) at amino acid position 182 to be replaced by an isoleucine (I). 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	0.099
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;T;.;.;T;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;D;D;D;D;D;T;D;D
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;T
Polyphen		0.90, 0.0010	.;.;.;P;.;.;.;B;.
Vest4		0.23, 0.29, 0.23, 0.23, 0.25
MutPred		0.63		.;.;.;Loss of catalytic residue at V181 (P = 0.0064);.;.;.;.;.;
MVP		0.082
MPC		0.14
ClinPred		0.87	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-99313135; COSMIC: COSV99217128;