chr2-86216945-A-G

Variant names:

• chr2-86216945-A-G
• rs141976852
• NM_001371279.1:c.*94T>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001371279.1(REEP1):​c.*94T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,019,268 control chromosomes in the GnomAD database, including 506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (69 hom., cov: 32)
  • Exomes 𝑓: 0.028 (437 hom.)
• Consequence: REEP1 NM_001371279.1 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.36

Genes affected

REEP1 (HGNC:25786): (receptor accessory protein 1) This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-86216945-A-G is Benign according to our data. Variant chr2-86216945-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}. Variant chr2-86216945-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3318/152272) while in subpopulation NFE AF= 0.0336 (2286/68022). AF 95% confidence interval is 0.0325. There are 69 homozygotes in gnomad4. There are 1577 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 69 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.*94T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924	c.*94T>C		3_prime_UTR_variant	Exon 9 of 9	5	NM_001371279.1	ENSP00000438346.3

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3318 AN: 152154 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0278 AC: 24094 AN: 866996 Hom.: 437 Cov.: 12 AF XY: 0.0270 AC XY: 12115 AN XY: 448970

Gnomad4 AFR exome AF: 0.00575

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000286

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0347

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0218 AC: 3318 AN: 152272 Hom.: 69 Cov.: 32 AF XY: 0.0212 AC XY: 1577 AN XY: 74470

Gnomad4 AFR AF: 0.00595

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0336

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0288 Hom.: 16

Bravo AF: 0.0198

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Jan 11, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 31 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Nov 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.83

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: rs141976852; hg19: chr2-86444068;