chr13-19432533-A-G

Variant names:

• chr13-19432533-A-G
• rs764470955
• NM_001395978.1:c.1162T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001395978.1(TPTE2):​c.1162T>C​(p.Trp388Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPTE2 NM_001395978.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0540
• Publications: 1 publications found

Genes affected

TPTE2 (HGNC:17299): (transmembrane phosphoinositide 3-phosphatase and tensin homolog 2) TPIP is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of inositol phospholipids.[supplied by OMIM, Jul 2002]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06552392).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395978.1. 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
	TPTE2	NM_001395978.1	MANE Select	c.1162T>C	p.Trp388Arg	missense	Exon 19 of 23	NP_001382907.1	Q6XPS3-1
	TPTE2	NM_199254.3		c.1162T>C	p.Trp388Arg	missense	Exon 17 of 21	NP_954863.2	Q6XPS3-1
	TPTE2	NM_130785.4		c.931T>C	p.Trp311Arg	missense	Exon 14 of 18	NP_570141.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPTE2	ENST00000697147.1	MANE Select	c.1162T>C	p.Trp388Arg	missense	Exon 19 of 23	ENSP00000513136.1	Q6XPS3-1
	TPTE2	ENST00000390680.2	TSL:1	c.931T>C	p.Trp311Arg	missense	Exon 14 of 18	ENSP00000375098.2	Q6XPS3-3
	TPTE2	ENST00000696858.2		c.1162T>C	p.Trp388Arg	missense	Exon 18 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248694 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000151 AC: 22 AN: 1455624 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 724136

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

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1109242

Other (OTH) AF: 0.00 AC: 0 AN: 60098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000636602), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.3
DANN	Benign	0.33
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.054
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.20
Sift	Benign	0.62	T
Sift4G	Benign	0.56	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.49		Gain of catalytic residue at P391 (P = 0)
MVP		0.28
MPC		0.47
ClinPred		0.045	T
GERP RS		-3.8
Varity_R		0.096
gMVP		0.57
Mutation Taster		=95/5	polymorphism

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: rs764470955; hg19: chr13-20006673;