14-102376694-G-A

Variant names:

• chr14-102376694-G-A
• rs184890979
• NM_014844.5:c.-28G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014844.5(TECPR2):​c.-28G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,602,996 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: TECPR2 NM_014844.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000308837 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 14-102376694-G-A is Benign according to our data. Variant chr14-102376694-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 509723.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0022 (335/152248) while in subpopulation AFR AF = 0.00753 (313/41558). AF 95% confidence interval is 0.00685. There are 3 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.-28G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 20	ENST00000359520.12	NP_055659.2
TECPR2	NM_014844.5	c.-28G>A		5_prime_UTR_variant	Exon 2 of 20	ENST00000359520.12	NP_055659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.-28G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 20	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000359520.12	c.-28G>A		5_prime_UTR_variant	Exon 2 of 20	1	NM_014844.5	ENSP00000352510.7

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152130 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000503 AC: 126 AN: 250744 AF XY: 0.000450

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000290 AC: 421 AN: 1450748 Hom.: 0 Cov.: 28 AF XY: 0.000275 AC XY: 199 AN XY: 722574

African (AFR) AF: 0.00749 AC: 249 AN: 33238

American (AMR) AF: 0.000269 AC: 12 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5744

European-Non Finnish (NFE) AF: 0.000106 AC: 117 AN: 1102036

Other (OTH) AF: 0.000617 AC: 37 AN: 60004

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74424

African (AFR) AF: 0.00753 AC: 313 AN: 41558

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.00234

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 31, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.13
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs184890979; hg19: chr14-102843031; COSMIC: COSV63974748;