rs200716334

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_018026.4(PACS1):​c.2358G>A​(p.Ser786Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,614,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PACS1
NM_018026.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 11-66239206-G-A is Benign according to our data. Variant chr11-66239206-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-5.48 with no splicing effect.
BS2
High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PACS1NM_018026.4 linkc.2358G>A p.Ser786Ser synonymous_variant Exon 21 of 24 ENST00000320580.9 NP_060496.2 Q6VY07-1A0A024R5H6
PACS1XM_011545162.2 linkc.2064G>A p.Ser688Ser synonymous_variant Exon 21 of 24 XP_011543464.2
PACS1XM_011545164.3 linkc.2019G>A p.Ser673Ser synonymous_variant Exon 21 of 24 XP_011543466.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PACS1ENST00000320580.9 linkc.2358G>A p.Ser786Ser synonymous_variant Exon 21 of 24 1 NM_018026.4 ENSP00000316454.4 Q6VY07-1
PACS1ENST00000529757.5 linkc.966G>A p.Ser322Ser synonymous_variant Exon 10 of 13 1 ENSP00000432858.1 B4DF77
PACS1ENST00000525798.1 linkn.396G>A non_coding_transcript_exon_variant Exon 2 of 3 2
PACS1ENST00000676419.1 linkn.395G>A non_coding_transcript_exon_variant Exon 6 of 6

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251298
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000199
AC:
291
AN:
1461744
Hom.:
0
Cov.:
31
AF XY:
0.000205
AC XY:
149
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000403
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000228
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152284
Hom.:
1
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000232
Hom.:
0
Bravo
AF:
0.000212
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000415

ClinVar

Significance: Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Aug 30, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PACS1: BP4, BP7 -

not specified Benign:1
Mar 13, 2017
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Jul 19, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PACS1-related disorder Benign:1
Jan 03, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schuurs-Hoeijmakers syndrome Benign:1
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
0.21
DANN
Benign
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs200716334; hg19: chr11-66006677; API