chr13-19430469-G-C

Variant names:

• chr13-19430469-G-C
• rs149205749
• NM_001395978.1:c.1301C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001395978.1(TPTE2):​c.1301C>G​(p.Ser434Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,606,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S434L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: TPTE2 NM_001395978.1 missense, splice_region
• Scores: Splicing: ADA: 0.0003499
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02
• Publications: 2 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011874646).

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.1301C>G	p.Ser434Trp	missense splice_region	Exon 20 of 23	NP_001382907.1	Q6XPS3-1
	TPTE2	NM_199254.3		c.1301C>G	p.Ser434Trp	missense splice_region	Exon 18 of 21	NP_954863.2	Q6XPS3-1
	TPTE2	NM_130785.4		c.1070C>G	p.Ser357Trp	missense splice_region	Exon 15 of 18	NP_570141.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPTE2	ENST00000697147.1	MANE Select	c.1301C>G	p.Ser434Trp	missense splice_region	Exon 20 of 23	ENSP00000513136.1	Q6XPS3-1
	TPTE2	ENST00000390680.2	TSL:1	c.1070C>G	p.Ser357Trp	missense splice_region	Exon 15 of 18	ENSP00000375098.2	Q6XPS3-3
	TPTE2	ENST00000696858.2		c.1301C>G	p.Ser434Trp	missense splice_region	Exon 19 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000448 AC: 109 AN: 243412 AF XY: 0.000410

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000341

Gnomad OTH exome AF: 0.000843

GnomAD4 exome AF: 0.000414 AC: 602 AN: 1454092 Hom.: 0 Cov.: 29 AF XY: 0.000412 AC XY: 298 AN XY: 723448

African (AFR) AF: 0.00112 AC: 37 AN: 33078

American (AMR) AF: 0.00131 AC: 56 AN: 42620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84590

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53332

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5728

European-Non Finnish (NFE) AF: 0.000408 AC: 452 AN: 1109166

Other (OTH) AF: 0.000666 AC: 40 AN: 60082

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74372

African (AFR) AF: 0.00101 AC: 42 AN: 41494

American (AMR) AF: 0.00190 AC: 29 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67996

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000986

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000818

EpiControl AF: 0.000297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.056
DANN	Benign	0.69
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.0
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.20
Sift	Benign	0.063	T
Sift4G	Uncertain	0.033	D
Polyphen		0.0040	B
Vest4		0.25
MVP		0.28
MPC		0.36
ClinPred		0.0067	T
GERP RS		-4.5
Varity_R		0.061
gMVP		0.54
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

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

Other links and lift over

dbSNP: rs149205749; hg19: chr13-20004609;