10-63566338-G-T

Variant names:

• chr10-63566338-G-T
• rs1197135444
• NM_001001330.3:c.33G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001001330.3(REEP3):​c.33G>T​(p.Val11Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: REEP3 NM_001001330.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.1481
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.052).
• BP6: Variant 10-63566338-G-T is Benign according to our data. Variant chr10-63566338-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3431960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3	c.33G>T	p.Val11Val	splice_region_variant, synonymous_variant	Exon 2 of 8	ENST00000373758.5	NP_001001330.1
REEP3	XM_011539501.3	c.33G>T	p.Val11Val	splice_region_variant, synonymous_variant	Exon 2 of 6		XP_011537803.1
REEP3	XM_017015896.2	c.33G>T	p.Val11Val	splice_region_variant, synonymous_variant	Exon 2 of 7		XP_016871385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP3	ENST00000373758.5	c.33G>T	p.Val11Val	splice_region_variant, synonymous_variant	Exon 2 of 8	1	NM_001001330.3	ENSP00000362863.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385454 Hom.: 0 Cov.: 26 AF XY: 0.00000146 AC XY: 1 AN XY: 684466

African (AFR) AF: 0.00 AC: 0 AN: 31510

American (AMR) AF: 0.00 AC: 0 AN: 35416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25066

East Asian (EAS) AF: 0.00 AC: 0 AN: 36530

South Asian (SAS) AF: 0.00 AC: 0 AN: 78110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066280

Other (OTH) AF: 0.00 AC: 0 AN: 57512

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 22, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.020		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

dbSNP: rs1197135444; hg19: chr10-65326098;