chr2-86216945-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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, Likely_benign=1, 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• 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 AC: 124 AN: 21562

Gnomad4 AMR exome AF: 0.0118 AC: 443 AN: 37476

Gnomad4 ASJ exome AF: 0.0122 AC: 263 AN: 21626

Gnomad4 EAS exome AF: 0.0000286 AC: 1 AN: 34964

Gnomad4 SAS exome AF: 0.00234 AC: 163 AN: 69704

Gnomad4 FIN exome AF: 0.0357 AC: 1800 AN: 50470

Gnomad4 NFE exome AF: 0.0347 AC: 20322 AN: 586004

Gnomad4 Remaining exome AF: 0.0230 AC: 935 AN: 40670

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 AC: 0.00594579 AN: 0.00594579

Gnomad4 AMR AF: 0.0161 AC: 0.0161459 AN: 0.0161459

Gnomad4 ASJ AF: 0.0138 AC: 0.0138249 AN: 0.0138249

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.00311 AC: 0.00310945 AN: 0.00310945

Gnomad4 FIN AF: 0.0332 AC: 0.0331825 AN: 0.0331825

Gnomad4 NFE AF: 0.0336 AC: 0.0336068 AN: 0.0336068

Gnomad4 OTH AF: 0.0204 AC: 0.0203598 AN: 0.0203598

Alfa AF: 0.0303 Hom.: 29

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
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs141976852; hg19: chr2-86444068;