rs750908377

Positions:

• chr14-102432029-CT-C

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.1319del​(p.Leu440ArgfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: TECPR2 NM_014844.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.09

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 14-102432029-CT-C is Pathogenic according to our data. Variant chr14-102432029-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 374308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102432029-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.1319del	p.Leu440ArgfsTer19	frameshift_variant	8/20	ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.1319del	p.Leu440ArgfsTer19	frameshift_variant	8/17		NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.1319del	p.Leu440ArgfsTer19	frameshift_variant	8/20	1	NM_014844.5	ENSP00000352510	P1
TECPR2	ENST00000558678.1	c.1319del	p.Leu440ArgfsTer19	frameshift_variant	8/17	1		ENSP00000453671

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 36 AN: 244296 Hom.: 0 AF XY: 0.000120 AC XY: 16 AN XY: 133456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00312

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000781 AC: 114 AN: 1460582 Hom.: 0 Cov.: 31 AF XY: 0.0000895 AC XY: 65 AN XY: 726604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 49 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 24, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 12, 2015	Our laboratory reported three molecular diagnoses in DFNA5 (NM_004403.2, c.119dup), FLG (NM_002016.1, c.4279G>A), and TECPR2 (NM_014844.3, c.1319del) in one individual with reported features which include delayed motor milestones, delayed speech, developmental regression, mild bilateral sensorineural hearing loss, hypotonia, hyporeflexia, dysmorphic features, short stature, hyperextensibility, ichthyosis, hypothyroidism, mild elevation of CK and eye anomalies. The c.1319del (p.L440fs) TECPR2 change has been reported in three unrelated Ashkenazi Jewish patients of non-Bukharian origin [PMID 26542466], either homozygous or compound heterozygous, leading to hereditary sensory-autonomic neuropathy. Heterozygotes are expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Jun 27, 2020	This homozygous variant was identified by (trio-)exome sequencing in three individuals (9 month old female, 2 year old male and 3 year old male) with developmental delay and muscular hypotonia. The families are from Ashkenazi Jewish descent. Each parents are heterozygous carriers for this variant. This frameshift variant c.1319del, p.(Leu440Argfs*19) in exon 8/20 of TECPR2 has a minor allel frequency in the general population of 0.0001342 (gnomAD). Two publications (PMID: 25590979, 26542466) report four similarly affected patients with this variant (homozygous or compound heterozygous). The variant is already reported in ClinVar as pathogenic (ID: 374308). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Leu440Argfs*19) 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 (rs750908377, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with autonomic dysfunction and intellectual disability (PMID: 25590979, 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: 374308). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 02, 2023

Variant summary: TECPR2 c.1319delT (p.Leu440ArgfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 244296 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TECPR2 causing Hereditary Spastic Paraplegia, Type 49 (0.00015 vs 0.0011), allowing no conclusion about variant significance. c.1319delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Spastic Paraplegia, Type 49 (e.g. Zhu_2015, Heimer_2016, Neuser_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26542466, 33847017, 25590979). Eight ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2022

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; This variant is associated with the following publications: (PMID: 33847017, 27959697, 26542466, 25590979, 32209221, 33884296) -

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: rs750908377; hg19: chr14-102898366;