rs11845676

chr14-102431867-G-Achr14-102431867-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014844.5(TECPR2):c.1156G>A(p.Ala386Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,603,288 control chromosomes in the GnomAD database, including 613 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (306 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (307 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.654

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 (MetaRNN=0.0017033517).
• BP6: Variant 14-102431867-G-A is Benign according to our data. Variant chr14-102431867-G-A is described in ClinVar as [Benign]. Clinvar id is 415302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102431867-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECPR2	NM_014844.5	c.1156G>A	p.Ala386Thr	missense_variant	8/20	ENST00000359520.12
TECPR2	NM_001172631.3	c.1156G>A	p.Ala386Thr	missense_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12	c.1156G>A	p.Ala386Thr	missense_variant	8/20	1	NM_014844.5	P1
TECPR2	ENST00000558678.1	c.1156G>A	p.Ala386Thr	missense_variant	8/17	1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5817 AN: 152204 Hom.: 306 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00561

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0138 AC: 3437 AN: 248572 Hom.: 135 AF XY: 0.0113 AC XY: 1521 AN XY: 134572

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00587

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00904 AC: 13115 AN: 1450966 Hom.: 307 Cov.: 31 AF XY: 0.00838 AC XY: 6027 AN XY: 719078

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00258

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00613

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0382 AC: 5822 AN: 152322 Hom.: 306 Cov.: 32 AF XY: 0.0370 AC XY: 2753 AN XY: 74484

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00562

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0113 Hom.: 80

Bravo AF: 0.0439

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.123 AC: 541

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.0157 AC: 1910

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.00763

EpiControl AF: 0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 49 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2017

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

Dec 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	5.7
Dann	Benign	0.96
DEOGEN2	Benign	0.0022	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.79	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.043
Sift	Benign	0.54	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0010	B;.
Vest4		0.021
MPC		0.30
ClinPred		0.0024	T
GERP RS		4.2
Varity_R		0.025
gMVP		0.26

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: rs11845676; hg19: chr14-102898204;