Genetic Variant TTPAL:p.Arg44Gln (chr20-44480130-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039199.3(TTPAL):c.131G>A(p.Arg44Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TTPAL
NM_001039199.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44

Variant links:

Genes affected

TTPAL (HGNC:16114): (alpha tocopherol transfer protein like) Predicted to enable phosphatidylinositol bisphosphate binding activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

TTPAL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPAL	NM_001039199.3 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 2 of 5	ENST00000262605.9	NP_001034288.1	Q9BTX7B2RA57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTPAL	ENST00000262605.9 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 2 of 5	1	NM_001039199.3	ENSP00000262605.4	Q9BTX7
TTPAL	ENST00000372904.7 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 3 of 6	1		ENSP00000361995.3	Q9BTX7
TTPAL	ENST00000456317.1 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 2 of 5	2		ENSP00000412720.1	Q5QPC2
TTPAL	ENST00000372906.2 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 2 of 3	3		ENSP00000361997.2	A6PVK2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251402

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131G>A (p.R44Q) alteration is located in exon 3 (coding exon 1) of the TTPAL gene. This alteration results from a G to A substitution at nucleotide position 131, causing the arginine (R) at amino acid position 44 to be replaced by a glutamine (Q). 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

0.11

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.014

T;T;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.90

L;L;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.026

D;D;D;D

Sift4G

Uncertain

0.032

D;D;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.64

MutPred

0.50

Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.23

MPC

1.3

ClinPred

0.79

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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