rs149363218

Variant names:

• chr21-10602053-CAT-C
• rs149363218
• NM_199261.4:c.1357-3_1357-2delTA

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05615942 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199261.4. 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
	TPTE	NM_199261.4	MANE Select	c.1357-3_1357-2delTA		splice_acceptor splice_region intron	N/A	NP_954870.3	P56180-1
	TPTE	NM_199259.4		c.1303-3_1303-2delTA		splice_acceptor splice_region intron	N/A	NP_954868.2	P56180-2
	TPTE	NM_199260.4		c.1243-3_1243-2delTA		splice_acceptor splice_region intron	N/A	NP_954869.2	P56180-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPTE	ENST00000618007.5	TSL:1 MANE Select	c.1357-4_1357-3delAT		splice_region intron	N/A	ENSP00000484403.1	P56180-1
	TPTE	ENST00000622113.4	TSL:1	c.1303-4_1303-3delAT		splice_region intron	N/A	ENSP00000482040.1	P56180-2
	TPTE	ENST00000427445.6	TSL:1	c.1243-4_1243-3delAT		splice_region intron	N/A	ENSP00000482488.1	P56180-3

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

GnomAD2 exomes AF: 0.00233 AC: 584 AN: 250150 AF XY: 0.00245

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00431

Gnomad OTH exome AF: 0.00295

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

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

African (AFR) AF: 0.000778 AC: 26 AN: 33398

American (AMR) AF: 0.00125 AC: 56 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86180

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53270

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00557 AC: 6132 AN: 1100886

Other (OTH) AF: 0.00497 AC: 298 AN: 59970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.000915 AC: 38 AN: 41522

American (AMR) AF: 0.00105 AC: 16 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00480 AC: 324 AN: 67484

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00506 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autism spectrum disorder;C2243051:Macrocephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
Mutation Taster		=57/43	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs149363218; hg19: chr21-10910404;