10-63619731-G-A

Variant names:

• chr10-63619731-G-A
• NM_001001330.3:c.642G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001001330.3(REEP3):​c.642G>A​(p.Met214Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP3 NM_001001330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2873683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3	c.642G>A	p.Met214Ile	missense_variant	Exon 7 of 8	ENST00000373758.5	NP_001001330.1
LOC105378329	XR_001747467.3	n.296-5039C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP3	ENST00000373758.5	c.642G>A	p.Met214Ile	missense_variant	Exon 7 of 8	1	NM_001001330.3	ENSP00000362863.4
REEP3	ENST00000634963.1	n.*226G>A		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000489394.1
REEP3	ENST00000634963.1	n.*226G>A		3_prime_UTR_variant	Exon 5 of 6	5		ENSP00000489394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.642G>A (p.M214I) alteration is located in exon 7 (coding exon 7) of the REEP3 gene. This alteration results from a G to A substitution at nucleotide position 642, causing the methionine (M) at amino acid position 214 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	Benign	0.19
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.039
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.29
Sift	Benign	0.35	T
Sift4G	Benign	0.21	T
Polyphen		0.15	B
Vest4		0.51
MutPred		0.22		Loss of ubiquitination at K218 (P = 0.0498);
MVP		0.85
MPC		0.37
ClinPred		0.67	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.50
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

hg19: chr10-65379491;