11-66211236-G-A

Position:

chr11-66211236-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_018026.4(PACS1):c.637G>A(p.Val213Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,613,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

PACS1
NM_018026.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.43

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 links:

PACS1 (HGNC:):

PACS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PACS1. . Gene score misZ 3.71 (greater than the threshold 3.09). Trascript score misZ 3.8723 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Schuurs-Hoeijmakers syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.10825655).

BP6

Variant 11-66211236-G-A is Benign according to our data. Variant chr11-66211236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66211236-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS1	NM_018026.4 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	4/24	ENST00000320580.9	NP_060496.2	Q6VY07-1A0A024R5H6
PACS1	XM_011545162.2 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	4/24		XP_011543464.2
PACS1	XM_011545164.3 linkuse as main transcript	c.298G>A	p.Val100Met	missense_variant	4/24		XP_011543466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PACS1	ENST00000320580.9 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	4/24	1	NM_018026.4	ENSP00000316454.4	Q6VY07-1
PACS1	ENST00000527380.1 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	4/5	4		ENSP00000432639.1	E9PPK2
PACS1	ENST00000527224.1 linkuse as main transcript	n.761G>A		non_coding_transcript_exon_variant	4/7	2
PACS1	ENST00000533756.5 linkuse as main transcript	c.*8G>A		downstream_gene_variant		4		ENSP00000437150.1	E9PNG7

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251160

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000255

AC:

372

AN:

1461342

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000282

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000402

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PACS1: PP2, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 21, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2016

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

T;T

Eigen

Benign

0.010

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0080

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.083

Sift

Benign

0.054

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.066

B;.

Vest4

0.32

MVP

0.34

MPC

1.4

ClinPred

0.036

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.24

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