Variant 9-101476144-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_032342.3(PGAP4):c.949C>T(p.Arg317Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PGAP4
NM_032342.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

Variant links:

Genes affected

PGAP4 (HGNC:28180): (post-GPI attachment to proteins GalNAc transferase 4) Enables glycosyltransferase activity. Involved in GPI anchor biosynthetic process. Located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

PGAP4 links:

TMEM246-AS1 (HGNC:51191): (TMEM246 antisense RNA 1)

TMEM246-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a mutagenesis_site Strongly reduces GPI-GalNAc transferase activity. Accumulates in the endoplasmic reticulum. (size 0) in uniprot entity PGAP4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP4	NM_032342.3 linkuse as main transcript	c.949C>T	p.Arg317Trp	missense_variant	2/2	ENST00000374848.8
TMEM246-AS1	NR_121573.1 linkuse as main transcript	n.337+1102G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP4	ENST00000374848.8 linkuse as main transcript	c.949C>T	p.Arg317Trp	missense_variant	2/2	1	NM_032342.3	P1
TMEM246-AS1	ENST00000424154.6 linkuse as main transcript	n.212-3696G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251114

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135700

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2023

The c.949C>T (p.R317W) alteration is located in exon 2 (coding exon 1) of the TMEM246 gene. This alteration results from a C to T substitution at nucleotide position 949, causing the arginine (R) at amino acid position 317 to be replaced by a tryptophan (W). 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

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.5

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.84

MutPred

0.50

Gain of catalytic residue at R317 (P = 0.0475);Gain of catalytic residue at R317 (P = 0.0475);Gain of catalytic residue at R317 (P = 0.0475);

MVP

0.28

MPC

1.2

ClinPred

0.95

GERP RS

5.7

Varity_R

0.63

gMVP

0.95

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