4-98379115-C-T

Position:

• chr4-98379115-C-T

Variant summary

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

The NM_001100427.2(RAP1GDS1):​c.460C>T​(p.Leu154Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,742 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: 0.0000014 (0 hom.)
• Consequence: RAP1GDS1 NM_001100427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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	Protein	UniProt
RAP1GDS1	NM_001100427.2	c.460C>T	p.Leu154Phe	missense_variant	5/15	ENST00000408927.8	NP_001093897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAP1GDS1	ENST00000408927.8	c.460C>T	p.Leu154Phe	missense_variant	5/15	2	NM_001100427.2	ENSP00000386153	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457742 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725106

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: 0.00000180

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

Jan 11, 2023

The c.463C>T (p.L155F) alteration is located in exon 5 (coding exon 5) of the RAP1GDS1 gene. This alteration results from a C to T substitution at nucleotide position 463, causing the leucine (L) at amino acid position 155 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.033	.;T;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.97	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N;N;D;N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T;T;D;T
Sift4G	Benign	0.064	T;T;T;D;T
Polyphen		1.0	.;D;.;.;.
Vest4		0.78, 0.81, 0.79
MutPred		0.47		.;Loss of stability (P = 0.0255);.;.;.;
MVP		0.38
MPC		0.70
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.58

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: chr4-99300266;