14-102497668-C-G

Variant names:

• chr14-102497668-C-G
• rs763133422
• NM_014844.5:c.4030C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014844.5(TECPR2):​c.4030C>G​(p.Pro1344Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,456,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.86

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.4030C>G	p.Pro1344Ala	missense_variant	Exon 19 of 20	ENST00000359520.12	NP_055659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.4030C>G	p.Pro1344Ala	missense_variant	Exon 19 of 20	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000559124.1	n.130C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
TECPR2	ENST00000561099.1	n.339C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000127 AC: 3 AN: 236446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456714 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000256 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 49 Uncertain:2

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with alanine at codon 1344 of the TECPR2 protein (p.Pro1344Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TECPR2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.64		Gain of catalytic residue at A1345 (P = 0.0056);
MVP		0.082
MPC		0.61
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.59

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: rs763133422; hg19: chr14-102964005;