rs751970061

Variant names:

• chr14-102452402-CT-C
• rs751970061
• NM_014844.5:c.3416delT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014844.5(TECPR2):​c.3416delT​(p.Leu1139ArgfsTer75) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TECPR2 NM_014844.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.42

Genes affected

TECPR2 (HGNC:19957): (tectonin beta-propeller repeat containing 2) The protein encoded by this gene is a member of the tectonin beta-propeller repeat-containing (TECPR) family, and contains both TECPR and tryptophan-aspartic acid repeat (WD repeat) domains. This gene has been implicated in autophagy, as reduced expression levels of this gene have been associated with impaired autophagy. Recessive mutations in this gene have been associated with a hereditary form of spastic paraparesis (HSP). HSP is characterized by progressive spasticity and paralysis of the legs. There is also some evidence linking mutations in this gene with birdshot chorioretinopathy (BSCR), which results in inflammation of the choroid and retina. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-102452402-CT-C is Pathogenic according to our data. Variant chr14-102452402-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102452402-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.3416delT	p.Leu1139ArgfsTer75	frameshift_variant	Exon 16 of 20	ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.3416delT	p.Leu1139ArgfsTer75	frameshift_variant	Exon 16 of 17		NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.3416delT	p.Leu1139ArgfsTer75	frameshift_variant	Exon 16 of 20	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000558678.1	c.3416delT	p.Leu1139ArgfsTer75	frameshift_variant	Exon 16 of 17	1		ENSP00000453671.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247472 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453630 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 721202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 49 Pathogenic:6

May 03, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu1139Argfs*75) in the TECPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TECPR2 are known to be pathogenic (PMID: 23176824, 25590979). This variant is present in population databases (rs751970061, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with complicated hereditary spastic paraplegia in Jewish Bukharian families or autonomic neuropathy with intellectual disability (PMID: 23176824, 26542466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39675). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 07, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 11, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been reported in homozygous state in five individuals of three families from Jewish Bukharian descent (PMID: 23176824). Additionally, the variant was identified in another individual in compound heterozygous state (with c.1319del, p.(Leu440Argfs*19) from Ashkenazi Jewish-Tunisian / Yamani-Kurdish descent (PMID: 26542466). All affected individuals displayed developmental delay, muscular hypotonia and symptoms of autonomic neuropathy. This frameshift variant c.3416del, p.(Leu1139Argfs*75) in exon 16/20 of TECPR2 has a minor allel frequency in the general population of 0.000008082 (gnomAD). The variant is already reported in ClinVar as pathogenic/likely pathogenic (ID: 39675). Biallelic truncating or missense variants have been described to cause "Spastic paraplegia 49, autosomal recessive" (Oz-Levi et al. Am J Hum Genet. 2012, PMID: 23176824). Taken together, we classify this variant as pathogenic based on the ACMG recommendations (Richards et al., 2015, PMID 25741868; criteria: PVS1 PS4_MOD PM2). -

Feb 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23176824, 32209221, 23439247, 33218264, 33847017, 26542466) -

Computational scores

Source: dbNSFP v4.3

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: rs751970061; hg19: chr14-102918739;