2-86214044-A-G

Variant names:

• chr2-86214044-A-G
• rs17438464
• NM_001371279.1:c.*2995T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001371279.1(REEP1):​c.*2995T>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 0.0162 in 199,976 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 33)
  • Exomes 𝑓: 0.019 (13 hom.)
• Consequence: REEP1 NM_001371279.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.426

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]

MRPL35 (HGNC:14489): (mitochondrial ribosomal protein L35) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Sequence analysis identified three transcript variants. Pseudogenes corresponding to this gene are found on chromosomes 6p, 10q, and Xp. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-86214044-A-G is Benign according to our data. Variant chr2-86214044-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 337343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0153 (2338/152364) while in subpopulation SAS AF= 0.0307 (148/4828). AF 95% confidence interval is 0.0266. There are 27 homozygotes in gnomad4. There are 1174 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.*2995T>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.*2995T>C		3_prime_UTR_variant	Exon 9 of 9	5	NM_001371279.1	ENSP00000438346.3
REEP1	ENST00000165698	c.*3056T>C		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000165698.5
REEP1	ENST00000646181.1	n.*207T>C		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2338 AN: 152246 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0181

GnomAD4 exome AF: 0.0191 AC: 909 AN: 47612 Hom.: 13 Cov.: 0 AF XY: 0.0196 AC XY: 492 AN XY: 25164

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.00720

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0153 AC: 2338 AN: 152364 Hom.: 27 Cov.: 33 AF XY: 0.0158 AC XY: 1174 AN XY: 74508

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0187 Hom.: 13

Bravo AF: 0.0139

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.78

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: rs17438464; hg19: chr2-86441167;