Genetic Variant PACS1:p.Gly15Glu (chr11-66070530-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018026.4(PACS1):c.44G>A(p.Gly15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PACS1
NM_018026.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

1 publications found

Variant links:

Genes affected

PACS1 (HGNC:30032): (phosphofurin acidic cluster sorting protein 1) This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance. [provided by RefSeq, Jul 2008]

PACS1 Gene-Disease associations (from GenCC):

Schuurs-Hoeijmakers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

PACS1 links:

ENSG00000255038 (HGNC:):

ENSG00000255038 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19840911).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018026.4. 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
	PACS1	NM_018026.4	MANE Select	c.44G>A	p.Gly15Glu	missense	Exon 1 of 24	NP_060496.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PACS1	ENST00000320580.9	TSL:1 MANE Select	c.44G>A	p.Gly15Glu	missense	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
PACS1	ENST00000527224.1	TSL:2	n.168G>A		non_coding_transcript_exon	Exon 1 of 7
ENSG00000255038	ENST00000830157.1		n.29+500C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

2270

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000170

AC:

AN:

1176884

Hom.:

Cov.:

AF XY:

0.00000175

AC XY:

AN XY:

570288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23182

American (AMR)

AF:

0.00

AC:

AN:

8758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15668

East Asian (EAS)

AF:

0.00

AC:

AN:

26716

South Asian (SAS)

AF:

0.0000232

AC:

AN:

43110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3244

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

980898

Other (OTH)

AF:

0.00

AC:

AN:

48048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.022

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.088

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.8

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.26

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.46

Vest4

0.37

MutPred

0.16

Loss of MoRF binding (P = 0.0741)

MVP

0.18

MPC

1.5

ClinPred

0.76

GERP RS

3.5

PromoterAI

0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.25

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over