Genetic Variant PGAP6:p.Arg690His (chr16-372234-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021259.3(PGAP6):c.2069G>A(p.Arg690His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,068 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 1 hom. )

Consequence

PGAP6
NM_021259.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.76

Variant links:

Genes affected

PGAP6 (HGNC:17205): (post-GPI attachment to proteins 6) Predicted to enable phospholipase A2 activity. Located in extracellular exosome and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

PGAP6 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
PGAP6	NM_021259.3 link	c.2069G>A	p.Arg690His	missense_variant	Exon 13 of 13	ENST00000431232.7	NP_067082.2	Q9HCN3
PGAP6	XM_047434413.1 link	c.1490G>A	p.Arg497His	missense_variant	Exon 14 of 14		XP_047290369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PGAP6	ENST00000431232.7 link	c.2069G>A	p.Arg690His	missense_variant	Exon 13 of 13	1	NM_021259.3	ENSP00000401338.2	Q9HCN3
PGAP6	ENST00000250930.7 link	c.1490G>A	p.Arg497His	missense_variant	Exon 13 of 13	2		ENSP00000250930.3	K4DI83
PGAP6	ENST00000424078.5 link	c.470G>A	p.Arg157His	missense_variant	Exon 4 of 4	3		ENSP00000397620.1	H0Y5B2
PGAP6	ENST00000448854.1 link	c.*308G>A		downstream_gene_variant		2		ENSP00000401931.1	H7C1S0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000966

AC:

AN:

248568

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1459942

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2069G>A (p.R690H) alteration is located in exon 13 (coding exon 13) of the TMEM8A gene. This alteration results from a G to A substitution at nucleotide position 2069, causing the arginine (R) at amino acid position 690 to be replaced by a histidine (H). 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

0.29

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.75

MutPred

0.57

Loss of MoRF binding (P = 0.0092);.;

MVP

0.78

MPC

0.32

ClinPred

0.70

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.67

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