NM_014844.5:c.1156G>A

Variant names:

• chr14-102431867-G-A
• rs11845676
• NM_014844.5:c.1156G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5
• Conservation: PhyloP100: 0.654
• Publications: 6 publications found

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]

TECPR2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 49

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 415302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	NM_014844.5	MANE Select	c.1156G>A	p.Ala386Thr	missense	Exon 8 of 20	NP_055659.2	O15040-1
	TECPR2	NM_001172631.3		c.1156G>A	p.Ala386Thr	missense	Exon 8 of 17	NP_001166102.1	O15040-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.1156G>A	p.Ala386Thr	missense	Exon 8 of 20	ENSP00000352510.7	O15040-1
	TECPR2	ENST00000558678.1	TSL:1	c.1156G>A	p.Ala386Thr	missense	Exon 8 of 17	ENSP00000453671.1	O15040-2
	TECPR2	ENST00000856897.1		c.1156G>A	p.Ala386Thr	missense	Exon 8 of 20	ENSP00000526956.1

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

GnomAD2 exomes AF: 0.0138 AC: 3437 AN: 248572 AF XY: 0.0113

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 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

African (AFR) AF: 0.121 AC: 4014 AN: 33272

American (AMR) AF: 0.0122 AC: 541 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 649 AN: 26056

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39354

South Asian (SAS) AF: 0.00258 AC: 222 AN: 85972

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53250

Middle Eastern (MID) AF: 0.00907 AC: 52 AN: 5732

European-Non Finnish (NFE) AF: 0.00613 AC: 6762 AN: 1103078

Other (OTH) AF: 0.0133 AC: 793 AN: 59778

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

African (AFR) AF: 0.119 AC: 4960 AN: 41564

American (AMR) AF: 0.0191 AC: 293 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10624

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00562 AC: 382 AN: 68032

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0136 Hom.: 163

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 49 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.79	N
PhyloP100		0.65
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.043
Sift	Benign	0.54	T
Sift4G	Benign	0.64	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11845676; hg19: chr14-102898204;