11-66070551-G-A

Position:

chr11-66070551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_018026.4(PACS1):c.65G>A(p.Gly22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,413,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

PACS1
NM_018026.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.13412979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS1	NM_018026.4 linkuse as main transcript	c.65G>A	p.Gly22Glu	missense_variant	1/24	ENST00000320580.9	NP_060496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS1	ENST00000320580.9 linkuse as main transcript	c.65G>A	p.Gly22Glu	missense_variant	1/24	1	NM_018026.4	ENSP00000316454	P2	Q6VY07-1
PACS1	ENST00000527224.1 linkuse as main transcript	n.189G>A		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

7.92e-7

AC:

AN:

1262102

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

620514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000158

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151708

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74088

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Schuurs-Hoeijmakers syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 22, 2021

The c.65G>A (p.Gly22Glu) variant identified in the PACS1 gene substitutes a moderately conserved Glycine for Glutamic Acid at amino acid 22/964 (exon 1/24). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes; allele frequency: 1.98e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the function of this variant, as it is predicted both Damaging (SIFT; score:0.00) and Benign (REVEL; 0.03099) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the c.65G>A (p.Gly22Glu) variant identified in the PACS1 gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.032

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.75

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.32

REVEL

Benign

0.031

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.036

Vest4

0.14

MutPred

0.33

Gain of solvent accessibility (P = 0.0145);

MVP

0.16

MPC

1.5

ClinPred

0.49

GERP RS

3.5

Varity_R

0.26

gMVP

0.21

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