chr5-112922099-C-A

Position:

• chr5-112922099-C-A

Variant summary

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

The NM_005669.5(REEP5):​c.92G>T​(p.Gly31Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP5 NM_005669.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

Genes affected

REEP5 (HGNC:30077): (receptor accessory protein 5) Predicted to be involved in endoplasmic reticulum organization and regulation of intracellular transport. Located in endoplasmic reticulum tubular network. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP5	NM_005669.5	c.92G>T	p.Gly31Val	missense_variant	1/5	ENST00000379638.9	NP_005660.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP5	ENST00000379638.9	c.92G>T	p.Gly31Val	missense_variant	1/5	1	NM_005669.5	ENSP00000368959.4
REEP5	ENST00000513339.5	c.92G>T	p.Gly31Val	missense_variant	1/4	2		ENSP00000425901.1
REEP5	ENST00000504247.1	c.92G>T	p.Gly31Val	missense_variant	1/3	5		ENSP00000421881.1
REEP5	ENST00000511865.6	n.131G>T		non_coding_transcript_exon_variant	1/6	2		ENSP00000421305.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 04, 2024

The c.92G>T (p.G31V) alteration is located in exon 1 (coding exon 1) of the REEP5 gene. This alteration results from a G to T substitution at nucleotide position 92, causing the glycine (G) at amino acid position 31 to be replaced by a valine (V). 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	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.66	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.68
MutPred		0.66		Loss of ubiquitination at K29 (P = 0.0524);Loss of ubiquitination at K29 (P = 0.0524);Loss of ubiquitination at K29 (P = 0.0524);
MVP		0.80
MPC		0.64
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.87

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: rs775139706; hg19: chr5-112257796;