10-63610304-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001330.3(REEP3):c.535A>G(p.Lys179Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000425 in 1,411,136 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: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: REEP3 NM_001001330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

Genes affected

REEP3 (HGNC:23711): (receptor accessory protein 3) Predicted to enable microtubule binding activity. Involved in mitotic nuclear membrane reassembly. Predicted to be integral component of membrane. Predicted to be active in cytoplasmic microtubule; endoplasmic reticulum membrane; and endoplasmic reticulum tubular network. [provided by Alliance of Genome Resources, Apr 2022]

LOC105378329 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22047588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP3	NM_001001330.3	c.535A>G	p.Lys179Glu	missense_variant	6/8	ENST00000373758.5
LOC105378329	XR_001747467.3	n.411+4273T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP3	ENST00000373758.5	c.535A>G	p.Lys179Glu	missense_variant	6/8	1	NM_001001330.3	P1
REEP3	ENST00000634963.1	c.*119A>G		3_prime_UTR_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1411136 Hom.: 0 Cov.: 31 AF XY: 0.00000574 AC XY: 4 AN XY: 697038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000461

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000872 AC: 1

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 08, 2023

The c.535A>G (p.K179E) alteration is located in exon 6 (coding exon 6) of the REEP3 gene. This alteration results from a A to G substitution at nucleotide position 535, causing the lysine (K) at amino acid position 179 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.065
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.20	T
Sift4G	Benign	0.95	T
Polyphen		0.65	P
Vest4		0.39
MutPred		0.21		Loss of ubiquitination at K179 (P = 0.0155);
MVP		0.87
MPC		0.47
ClinPred		0.58	D
GERP RS		6.0
Varity_R		0.17
gMVP		0.17

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: rs755466573; hg19: chr10-65370064;