chr14-102428245-G-T

Variant names:

• chr14-102428245-G-T
• rs55716270
• NM_014844.5:c.952-5G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_014844.5(TECPR2):​c.952-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.13 (22 hom.)
  • Failed GnomAD Quality Control
• Consequence: TECPR2 NM_014844.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004718
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.377
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-102428245-G-T is Benign according to our data. Variant chr14-102428245-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 702193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.952-5G>T		splice_region_variant, intron_variant	Intron 6 of 19	ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.952-5G>T		splice_region_variant, intron_variant	Intron 6 of 16		NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.952-5G>T		splice_region_variant, intron_variant	Intron 6 of 19	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000558678.1	c.952-5G>T		splice_region_variant, intron_variant	Intron 6 of 16	1		ENSP00000453671.1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 1020 AN: 25938 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0313

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0328

GnomAD2 exomes AF: 0.00449 AC: 98 AN: 21844 AF XY: 0.00434

Gnomad AFR exome AF: 0.00692

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00672

Gnomad FIN exome AF: 0.000935

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.132 AC: 62206 AN: 472908 Hom.: 22 Cov.: 17 AF XY: 0.128 AC XY: 29602 AN XY: 231568

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.104 AC: 1088 AN: 10422

American (AMR) AF: 0.0226 AC: 154 AN: 6802

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 465 AN: 8822

East Asian (EAS) AF: 0.0124 AC: 228 AN: 18366

South Asian (SAS) AF: 0.150 AC: 1961 AN: 13046

European-Finnish (FIN) AF: 0.00997 AC: 217 AN: 21768

Middle Eastern (MID) AF: 0.0848 AC: 144 AN: 1698

European-Non Finnish (NFE) AF: 0.151 AC: 55831 AN: 370522

Other (OTH) AF: 0.0987 AC: 2118 AN: 21462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0393 AC: 1020 AN: 25954 Hom.: 0 Cov.: 0 AF XY: 0.0359 AC XY: 449 AN XY: 12498

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0386 AC: 272 AN: 7040

American (AMR) AF: 0.0293 AC: 68 AN: 2320

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 20 AN: 638

East Asian (EAS) AF: 0.0217 AC: 24 AN: 1106

South Asian (SAS) AF: 0.0519 AC: 47 AN: 906

European-Finnish (FIN) AF: 0.0135 AC: 14 AN: 1034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.0453 AC: 559 AN: 12340

Other (OTH) AF: 0.0319 AC: 12 AN: 376

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary spastic paraplegia 49 Benign:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.9
DANN	Benign	0.76
PhyloP100		-0.38
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.010
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: rs55716270; hg19: chr14-102894582;