dbSNP rs370210322: PTTG1IP:p.Gly4Arg (chr21-44873607-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004339.4(PTTG1IP):c.10G>A(p.Gly4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,436,238 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00058 ( 3 hom. )

Consequence

PTTG1IP
NM_004339.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.927

Variant links:

Genes affected

PTTG1IP (HGNC:13524): (PTTG1 interacting protein) This gene encodes a single-pass type I integral membrane protein, which binds to pituitary tumor-transforming 1 protein (PTTG1), and facilitates translocation of PTTG1 into the nucleus. Coexpression of this protein and PTTG1 induces transcriptional activation of basic fibroblast growth factor. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

PTTG1IP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00754869).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTTG1IP	NM_004339.4 link	c.10G>A	p.Gly4Arg	missense_variant	Exon 1 of 6	ENST00000330938.8	NP_004330.1	P53801
PTTG1IP	NM_001286822.2 link	c.10G>A	p.Gly4Arg	missense_variant	Exon 1 of 3		NP_001273751.1	P53801B4DPZ0
PTTG1IP	NR_104597.2 link	n.84G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTTG1IP	ENST00000330938.8 link	c.10G>A	p.Gly4Arg	missense_variant	Exon 1 of 6	1	NM_004339.4	ENSP00000328325.3	P53801
PTTG1IP	ENST00000445724.3 link	c.10G>A	p.Gly4Arg	missense_variant	Exon 1 of 3	2		ENSP00000395374.2	B4DPZ0
PTTG1IP	ENST00000397887.7 link	c.10G>A	p.Gly4Arg	missense_variant	Exon 1 of 4	4		ENSP00000380984.3	A8MZH8
PTTG1IP	ENST00000480234.1 link	n.62G>A		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000857

AC:

AN:

61816

Hom.:

AF XY:

0.000768

AC XY:

AN XY:

36472

show subpopulations

Gnomad AFR exome

AF:

0.00270

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000178

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000352

Gnomad FIN exome

AF:

0.000230

Gnomad NFE exome

AF:

0.000861

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.000585

AC:

751

AN:

1284008

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

351

AN XY:

632430

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.0000454

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000189

Gnomad4 FIN exome

AF:

0.0000943

Gnomad4 NFE exome

AF:

0.000531

Gnomad4 OTH exome

AF:

0.00135

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152230

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000723

Hom.:

Bravo

AF:

0.00137

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00114

AC:

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10G>A (p.G4R) alteration is located in exon 1 (coding exon 1) of the PTTG1IP gene. This alteration results from a G to A substitution at nucleotide position 10, causing the glycine (G) at amino acid position 4 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.024

.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.5

N;N;D

REVEL

Benign

0.011

Sift

Benign

0.050

D;T;T

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.0010, 0.062

.;B;B

Vest4

0.12

MutPred

0.30

Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);

MVP

0.085

MPC

0.31

ClinPred

0.00042

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.30

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over