4-98379127-T-A

Variant names:

• chr4-98379127-T-A
• NM_001100427.2:c.472T>A

Variant summary

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

The NM_001100427.2(RAP1GDS1):​c.472T>A​(p.Phe158Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAP1GDS1 NM_001100427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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 rank	MANE	Protein	UniProt
RAP1GDS1	NM_001100427.2	c.472T>A	p.Phe158Ile	missense_variant	Exon 5 of 15	ENST00000408927.8	NP_001093897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1GDS1	ENST00000408927.8	c.472T>A	p.Phe158Ile	missense_variant	Exon 5 of 15	2	NM_001100427.2	ENSP00000386153.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475T>A (p.F159I) alteration is located in exon 5 (coding exon 5) of the RAP1GDS1 gene. This alteration results from a T to A substitution at nucleotide position 475, causing the phenylalanine (F) at amino acid position 159 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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;T;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	.;L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.52	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.54	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.98	.;D;.;.;.
Vest4		0.75, 0.76
MutPred		0.47		.;Loss of catalytic residue at F158 (P = 0.0673);.;.;.;
MVP		0.50
MPC		0.32
ClinPred		0.91	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.25
gMVP		0.67

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: chr4-99300278;