rs55716270

Positions:

• chr14-102428245-G-A
• chr14-102428245-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014844.5(TECPR2):​c.952-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (30 hom.)
• Consequence: TECPR2 NM_014844.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004091
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.377

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 14-102428245-G-A is Benign according to our data. Variant chr14-102428245-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102428245-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00848 (226/26640) while in subpopulation NFE AF= 0.0136 (173/12714). AF 95% confidence interval is 0.012. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.952-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.952-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.952-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014844.5	ENSP00000352510	P1
TECPR2	ENST00000558678.1	c.952-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000453671

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 226 AN: 26624 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0988

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0109

GnomAD3 exomes AF: 0.00348 AC: 76 AN: 21844 Hom.: 3 AF XY: 0.00400 AC XY: 48 AN XY: 11990

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00922

GnomAD4 exome AF: 0.00566 AC: 3204 AN: 565598 Hom.: 30 Cov.: 17 AF XY: 0.00541 AC XY: 1489 AN XY: 275256

Gnomad4 AFR exome AF: 0.000489

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000133

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00668

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00848 AC: 226 AN: 26640 Hom.: 0 Cov.: 0 AF XY: 0.00797 AC XY: 102 AN XY: 12790

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.00463

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0106

Alfa AF: 0.000535 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TECPR2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2021

- -

TECPR2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia 49 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.3
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
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: rs55716270; hg19: chr14-102894582;