4-98416878-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001100427.2(RAP1GDS1):c.897A>C(p.Leu299Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,102 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: 0.0000027 (0 hom.)
• Consequence: RAP1GDS1 NM_001100427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1GDS1	NM_001100427.2	c.897A>C	p.Leu299Phe	missense_variant	8/15	ENST00000408927.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1GDS1	ENST00000408927.8	c.897A>C	p.Leu299Phe	missense_variant	8/15	2	NM_001100427.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246992 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460102 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726384

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

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

Dec 21, 2022

The c.900A>C (p.L300F) alteration is located in exon 8 (coding exon 8) of the RAP1GDS1 gene. This alteration results from a A to C substitution at nucleotide position 900, causing the leucine (L) at amino acid position 300 to be replaced by a phenylalanine (F). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;D;.;D;.
Vest4		0.71
MutPred		0.66		.;.;Loss of helix (P = 0.1299);.;.;.;
MVP		0.74
MPC		0.73
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.64
gMVP		0.48

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: rs1406124394; hg19: chr4-99338029;