5-112922129-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005669.5(REEP5):c.62A>G(p.Asp21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: REEP5 NM_005669.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26994556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP5	NM_005669.5	c.62A>G	p.Asp21Gly	missense_variant	1/5	ENST00000379638.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP5	ENST00000379638.9	c.62A>G	p.Asp21Gly	missense_variant	1/5	1	NM_005669.5	P1
REEP5	ENST00000513339.5	c.62A>G	p.Asp21Gly	missense_variant	1/4	2
REEP5	ENST00000504247.1	c.62A>G	p.Asp21Gly	missense_variant	1/3	5
REEP5	ENST00000511865.6	c.104A>G	p.Asp35Gly	missense_variant, NMD_transcript_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454518 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723586

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.: 31

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

Feb 28, 2023

The c.62A>G (p.D21G) alteration is located in exon 1 (coding exon 1) of the REEP5 gene. This alteration results from a A to G substitution at nucleotide position 62, causing the aspartic acid (D) at amino acid position 21 to be replaced by a glycine (G). 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	Benign	0.28
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.017	D;T;T
Sift4G	Benign	0.13	T;T;D
Polyphen		0.0030	B;P;.
Vest4		0.37
MutPred		0.34		Loss of ubiquitination at K16 (P = 0.046);Loss of ubiquitination at K16 (P = 0.046);Loss of ubiquitination at K16 (P = 0.046);
MVP		0.42
MPC		0.20
ClinPred		0.94	D
GERP RS		3.1
Varity_R		0.63
gMVP		0.71

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: rs922299171; hg19: chr5-112257826;