11-66233873-G-T

Position:

• chr11-66233873-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_018026.4(PACS1):​c.1927G>T​(p.Val643Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PACS1 NM_018026.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.75

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS1	NM_018026.4	c.1927G>T	p.Val643Phe	missense_variant	16/24	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.1633G>T	p.Val545Phe	missense_variant	16/24		XP_011543464.2
PACS1	XM_011545164.3	c.1588G>T	p.Val530Phe	missense_variant	16/24		XP_011543466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS1	ENST00000320580.9	c.1927G>T	p.Val643Phe	missense_variant	16/24	1	NM_018026.4	ENSP00000316454.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 22, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2017

The V643F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V643F variant is not observed in large population cohorts (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with PACS1-related disorders (Stenson et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.071	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.64		Loss of MoRF binding (P = 0.0977);.;.;
MVP		0.85
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.97

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

Other links and lift over

dbSNP: rs1554993495; hg19: chr11-66001344;