Genetic Variant PACS1:p.Pro32Gln (chr11-66070581-C-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.95C>A(p.Pro32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,341,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

PACS1
NM_018026.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0870

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen

PACS1 links:

ENSG00000255038 (HGNC:):

ENSG00000255038 links:

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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=0.07230052).

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.95C>A	p.Pro32Gln	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.95C>A	p.Pro32Gln	missense	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
PACS1	ENST00000527224.1	TSL:2	n.219C>A		non_coding_transcript_exon	Exon 1 of 7
ENSG00000255038	ENST00000830157.1		n.29+449G>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000105

AC:

AN:

94962

AF XY:

0.0000185

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000298

AC:

AN:

1341894

Hom.:

Cov.:

AF XY:

0.00000453

AC XY:

AN XY:

662338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27240

American (AMR)

AF:

0.00

AC:

AN:

31052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23558

East Asian (EAS)

AF:

0.00

AC:

AN:

29758

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4184

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1061004

Other (OTH)

AF:

0.00

AC:

AN:

55874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.1

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.024

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.39

M_CAP

Benign

0.025

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

-0.087

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.17

REVEL

Benign

0.036

Sift

Pathogenic

0.0

Sift4G

Benign

0.53

Polyphen

0.0030

Vest4

0.25

MutPred

0.29

Loss of glycosylation at P32 (P = 0.0022)

MVP

0.18

MPC

1.1

ClinPred

0.20

GERP RS

-3.7

PromoterAI

0.0053

Neutral

(source)

Varity_R

0.093

gMVP

0.067

Mutation Taster

=97/3

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