rs75004775

Positions:

• chr14-102452452-C-A
• chr14-102452452-C-G
• chr14-102452452-C-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.3465C>A​(p.Ser1155Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000744 in 1,613,698 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1155S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (14 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.856

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=0.0030600429).
• BP6: Variant 14-102452452-C-A is Benign according to our data. Variant chr14-102452452-C-A is described in ClinVar as [Benign]. Clinvar id is 473091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102452452-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000741 (113/152394) while in subpopulation EAS AF= 0.0179 (93/5184). AF 95% confidence interval is 0.015. There are 4 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECPR2	NM_014844.5	c.3465C>A	p.Ser1155Arg	missense_variant	16/20	ENST00000359520.12
TECPR2	NM_001172631.3	c.3465C>A	p.Ser1155Arg	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12	c.3465C>A	p.Ser1155Arg	missense_variant	16/20	1	NM_014844.5	P1
TECPR2	ENST00000558678.1	c.3465C>A	p.Ser1155Arg	missense_variant	16/17	1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152276 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0179

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00158 AC: 391 AN: 248182 Hom.: 7 AF XY: 0.00159 AC XY: 214 AN XY: 134604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0174

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000744 AC: 1087 AN: 1461304 Hom.: 14 Cov.: 33 AF XY: 0.000763 AC XY: 555 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0210

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000741 AC: 113 AN: 152394 Hom.: 4 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74522

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0179

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000895

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.14
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.072
Sift	Uncertain	0.016	D;T
Sift4G	Uncertain	0.048	D;T
Polyphen		0.45	B;.
Vest4		0.41
MutPred		0.30		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.068
MPC		0.37
ClinPred		0.018	T
GERP RS		-7.6
Varity_R		0.076
gMVP		0.16

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: rs75004775; hg19: chr14-102918789;