chr9-35750244-G-A

Position:

• chr9-35750244-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001080496.3(RGP1):​c.118G>A​(p.Glu40Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGP1 NM_001080496.3 missense, splice_region
• Scores: Splicing: ADA: 0.9658
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

Genes affected

RGP1 (HGNC:21965): (RGP1 homolog, RAB6A GEF complex partner 1) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in negative regulation of cellular protein catabolic process; positive regulation of GTPase activity; and retrograde transport, endosome to Golgi. Located in cytosol and plasma membrane. Part of Ric1-Rgp1 guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

RGP1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGP1	NM_001080496.3	c.118G>A	p.Glu40Lys	missense_variant, splice_region_variant	3/9	ENST00000378078.5	NP_001073965.2
RGP1	XR_007061382.1	n.259G>A		splice_region_variant, non_coding_transcript_exon_variant	3/12
RGP1	XR_007061383.1	n.259G>A		splice_region_variant, non_coding_transcript_exon_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGP1	ENST00000378078.5	c.118G>A	p.Glu40Lys	missense_variant, splice_region_variant	3/9	1	NM_001080496.3	ENSP00000367318.4
RGP1	ENST00000496906.1	n.255G>A		splice_region_variant, non_coding_transcript_exon_variant	3/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Aug 20, 2024

The c.118G>A (p.E40K) alteration is located in exon 3 (coding exon 2) of the RGP1 gene. This alteration results from a G to A substitution at nucleotide position 118, causing the glutamic acid (E) at amino acid position 40 to be replaced by a lysine (K). 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	0.92
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0093	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.056	T
Polyphen		0.96	D
Vest4		0.66
MutPred		0.81		Gain of ubiquitination at E40 (P = 0.0117);
MVP		0.37
MPC		0.76
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.71
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 3

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: chr9-35750241;