14-102434431-A-G

Variant names:

• chr14-102434431-A-G
• rs17791240
• NM_014844.5:c.1614A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014844.5(TECPR2):​c.1614A>G​(p.Pro538Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,531,524 control chromosomes in the GnomAD database, including 1,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (158 hom., cov: 32)
  • Exomes 𝑓: 0.033 (864 hom.)
• Consequence: TECPR2 NM_014844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.191
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-102434431-A-G is Benign according to our data. Variant chr14-102434431-A-G is described in ClinVar as Benign. ClinVar VariationId is 380928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	NM_014844.5	MANE Select	c.1614A>G	p.Pro538Pro	synonymous	Exon 9 of 20	NP_055659.2
	TECPR2	NM_001172631.3		c.1614A>G	p.Pro538Pro	synonymous	Exon 9 of 17	NP_001166102.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.1614A>G	p.Pro538Pro	synonymous	Exon 9 of 20	ENSP00000352510.7
	TECPR2	ENST00000558678.1	TSL:1	c.1614A>G	p.Pro538Pro	synonymous	Exon 9 of 17	ENSP00000453671.1

Frequencies

GnomAD3 genomes AF: 0.0418 AC: 6354 AN: 152170 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0525

GnomAD2 exomes AF: 0.0382 AC: 7094 AN: 185558 AF XY: 0.0371

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.0464

Gnomad EAS exome AF: 0.0291

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0332 AC: 45805 AN: 1379236 Hom.: 864 Cov.: 30 AF XY: 0.0330 AC XY: 22373 AN XY: 677666

African (AFR) AF: 0.0544 AC: 1669 AN: 30690

American (AMR) AF: 0.0563 AC: 1752 AN: 31116

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 955 AN: 20474

East Asian (EAS) AF: 0.0403 AC: 1575 AN: 39064

South Asian (SAS) AF: 0.0383 AC: 2769 AN: 72308

European-Finnish (FIN) AF: 0.0389 AC: 1953 AN: 50244

Middle Eastern (MID) AF: 0.0516 AC: 277 AN: 5366

European-Non Finnish (NFE) AF: 0.0306 AC: 32845 AN: 1073222

Other (OTH) AF: 0.0354 AC: 2010 AN: 56752

GnomAD4 genome AF: 0.0418 AC: 6363 AN: 152288 Hom.: 158 Cov.: 32 AF XY: 0.0417 AC XY: 3107 AN XY: 74474

African (AFR) AF: 0.0573 AC: 2380 AN: 41548

American (AMR) AF: 0.0451 AC: 690 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5174

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4828

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10622

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0314 AC: 2135 AN: 68026

Other (OTH) AF: 0.0529 AC: 112 AN: 2116

Alfa AF: 0.0361 Hom.: 239

Bravo AF: 0.0433

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.85
DANN	Benign	0.36
PhyloP100		-0.19
Mutation Taster		=100/0	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: rs17791240; hg19: chr14-102900768;