rs139314486

Positions:

• chr14-102498110-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014844.5(TECPR2):​c.4089G>A​(p.Ala1363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,388 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: TECPR2 NM_014844.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.927

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-102498110-G-A is Benign according to our data. Variant chr14-102498110-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102498110-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.927 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECPR2	NM_014844.5	c.4089G>A	p.Ala1363=	synonymous_variant	20/20	ENST00000359520.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12	c.4089G>A	p.Ala1363=	synonymous_variant	20/20	1	NM_014844.5	P1
TECPR2	ENST00000559124.1	n.189G>A		non_coding_transcript_exon_variant	2/2	2
TECPR2	ENST00000561099.1	n.398G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00152 AC: 378 AN: 249462 Hom.: 0 AF XY: 0.00159 AC XY: 215 AN XY: 135042

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00349

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.0000942

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00206 AC: 3008 AN: 1461078 Hom.: 9 Cov.: 37 AF XY: 0.00206 AC XY: 1494 AN XY: 726848

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74484

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00154

ClinVar

Significance: Benign/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	GeneDx	Oct 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TECPR2: BP4, BP7 -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2018

- -

TECPR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs139314486; hg19: chr14-102964447;