rs149363218

Positions:

• chr21-10602053-CAT-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_199261.4(TPTE):​c.1357-3_1357-2delTA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 151,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 81)
  • Exomes 𝑓: 0.0046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPTE NM_199261.4 splice_acceptor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.818

Genes affected

TPTE (HGNC:12023): (transmembrane phosphatase with tensin homology) This gene encodes a PTEN-related tyrosine phosphatase which may play a role in the signal transduction pathways of the endocrine or spermatogenic function of the testis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ENSG00000273840 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.055555556 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 0 (no position change), new splice context is: aattccatgtgttcattcAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPTE	NM_199261.4	c.1357-3_1357-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000618007.5	NP_954870.3
TPTE	NM_199259.4	c.1303-3_1303-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant			NP_954868.2
TPTE	NM_199260.4	c.1243-3_1243-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant			NP_954869.2
TPTE	NM_001290224.2	c.943-3_943-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant			NP_001277153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPTE	ENST00000618007.5	c.1357-3_1357-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_199261.4	ENSP00000484403.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 413 AN: 151544 Hom.: 0 Cov.: 81

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.0218

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00336

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00457 AC: 6623 AN: 1449832 Hom.: 0 AF XY: 0.00440 AC XY: 3174 AN XY: 721566

Gnomad4 AFR exome AF: 0.000778

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00557

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00272 AC: 413 AN: 151662 Hom.: 0 Cov.: 81 AF XY: 0.00242 AC XY: 180 AN XY: 74232

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00480

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00506 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder;C2243051:Macrocephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Abrahams Lab, Albert Einstein College of Medicine

Dec 22, 2014

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149363218; hg19: chr21-10910404;