rs17438464

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371279.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	NM_001371279.1	MANE Select	c.*2995T>C		3_prime_UTR	Exon 9 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.*2995T>C		3_prime_UTR	Exon 8 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.*3056T>C		3_prime_UTR	Exon 8 of 8	NP_001397785.1	A0A8I5QKJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.*2995T>C		3_prime_UTR	Exon 9 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.*3056T>C		3_prime_UTR	Exon 7 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000908467.1		c.*2995T>C		3_prime_UTR	Exon 9 of 9	ENSP00000578526.1

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

African (AFR) AF: 0.00294 AC: 3 AN: 1020

American (AMR) AF: 0.0149 AC: 33 AN: 2216

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 10 AN: 1388

East Asian (EAS) AF: 0.00 AC: 0 AN: 2134

South Asian (SAS) AF: 0.0311 AC: 180 AN: 5784

European-Finnish (FIN) AF: 0.0195 AC: 50 AN: 2564

Middle Eastern (MID) AF: 0.0150 AC: 3 AN: 200

European-Non Finnish (NFE) AF: 0.0197 AC: 581 AN: 29552

Other (OTH) AF: 0.0178 AC: 49 AN: 2754

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

African (AFR) AF: 0.00380 AC: 158 AN: 41586

American (AMR) AF: 0.0146 AC: 224 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4828

European-Finnish (FIN) AF: 0.0238 AC: 253 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1483 AN: 68040

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0182 Hom.: 15

Bravo AF: 0.0139

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 31 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		0.43
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

Other links and lift over

dbSNP: rs17438464; hg19: chr2-86441167;