NM_001395978.1:c.1220G>C

Variant names:

• chr13-19432475-C-G
• rs140778301
• NM_001395978.1:c.1220G>C

Variant summary

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

The NM_001395978.1(TPTE2):​c.1220G>C​(p.Arg407Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000922 in 1,573,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R407C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: TPTE2 NM_001395978.1 missense, splice_region
• Scores: Splicing: ADA: 0.000009329
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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=0.03864947).

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.1220G>C	p.Arg407Pro	missense splice_region	Exon 19 of 23	NP_001382907.1	Q6XPS3-1
	TPTE2	NM_199254.3		c.1220G>C	p.Arg407Pro	missense splice_region	Exon 17 of 21	NP_954863.2	Q6XPS3-1
	TPTE2	NM_130785.4		c.989G>C	p.Arg330Pro	missense splice_region	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.1220G>C	p.Arg407Pro	missense splice_region	Exon 19 of 23	ENSP00000513136.1	Q6XPS3-1
	TPTE2	ENST00000390680.2	TSL:1	c.989G>C	p.Arg330Pro	missense splice_region	Exon 14 of 18	ENSP00000375098.2	Q6XPS3-3
	TPTE2	ENST00000696858.2		c.1220G>C	p.Arg407Pro	missense splice_region	Exon 18 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes AF: 0.0000706 AC: 9 AN: 127390 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000850

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000233

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000168

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 45 AN: 246472 AF XY: 0.000225

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000941 AC: 136 AN: 1445658 Hom.: 0 Cov.: 29 AF XY: 0.000131 AC XY: 94 AN XY: 719220

African (AFR) AF: 0.0000604 AC: 2 AN: 33120

American (AMR) AF: 0.0000227 AC: 1 AN: 44086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39036

South Asian (SAS) AF: 0.00134 AC: 114 AN: 84876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52478

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4594

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102130

Other (OTH) AF: 0.0000840 AC: 5 AN: 59542

GnomAD4 genome AF: 0.0000706 AC: 9 AN: 127496 Hom.: 0 Cov.: 20 AF XY: 0.0000821 AC XY: 5 AN XY: 60870

African (AFR) AF: 0.0000847 AC: 3 AN: 35426

American (AMR) AF: 0.00 AC: 0 AN: 11620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3120

East Asian (EAS) AF: 0.000234 AC: 1 AN: 4282

South Asian (SAS) AF: 0.00116 AC: 4 AN: 3444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.0000168 AC: 1 AN: 59676

Other (OTH) AF: 0.00 AC: 0 AN: 1678

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000165 AC: 20

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	Benign	0.22
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.36
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.080	N
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.30
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.50
MutPred		0.56		Gain of catalytic residue at S405 (P = 0)
MVP		0.41
MPC		0.38
ClinPred		0.036	T
GERP RS		1.4
Varity_R		0.26
gMVP		0.47
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000093
dbscSNV1_RF	Benign	0.0020
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: rs140778301; hg19: chr13-20006615;