rs17791240

Positions:

• chr14-102434431-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014844.5(TECPR2):​c.1614A>G​(p.Pro538Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,531,524 control chromosomes in the GnomAD database, including 1,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (158 hom., cov: 32)
  • Exomes 𝑓: 0.033 (864 hom.)
• Consequence: TECPR2 NM_014844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.191

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-102434431-A-G is Benign according to our data. Variant chr14-102434431-A-G is described in ClinVar as [Benign]. Clinvar id is 380928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102434431-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.1614A>G	p.Pro538Pro	synonymous_variant	9/20	ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.1614A>G	p.Pro538Pro	synonymous_variant	9/17		NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.1614A>G	p.Pro538Pro	synonymous_variant	9/20	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000558678.1	c.1614A>G	p.Pro538Pro	synonymous_variant	9/17	1		ENSP00000453671.1

Frequencies

GnomAD3 genomes AF: 0.0418 AC: 6354 AN: 152170 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0525

GnomAD3 exomes AF: 0.0382 AC: 7094 AN: 185558 Hom.: 162 AF XY: 0.0371 AC XY: 3624 AN XY: 97802

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.0464

Gnomad EAS exome AF: 0.0291

Gnomad SAS exome AF: 0.0375

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0332 AC: 45805 AN: 1379236 Hom.: 864 Cov.: 30 AF XY: 0.0330 AC XY: 22373 AN XY: 677666

Gnomad4 AFR exome AF: 0.0544

Gnomad4 AMR exome AF: 0.0563

Gnomad4 ASJ exome AF: 0.0466

Gnomad4 EAS exome AF: 0.0403

Gnomad4 SAS exome AF: 0.0383

Gnomad4 FIN exome AF: 0.0389

Gnomad4 NFE exome AF: 0.0306

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0418 AC: 6363 AN: 152288 Hom.: 158 Cov.: 32 AF XY: 0.0417 AC XY: 3107 AN XY: 74474

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.0451

Gnomad4 ASJ AF: 0.0455

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.0408

Gnomad4 NFE AF: 0.0314

Gnomad4 OTH AF: 0.0529

Alfa AF: 0.0351 Hom.: 177

Bravo AF: 0.0433

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 15, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary spastic paraplegia 49 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.85
DANN	Benign	0.36

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: rs17791240; hg19: chr14-102900768;