11-66070590-A-C

Position:

• chr11-66070590-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_018026.4(PACS1):​c.104A>C​(p.Gln35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,397,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: PACS1 NM_018026.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.163

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]

ACMG classification

Verdict is Benign. Variant got -8 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=0.005846381).
• BP6: Variant 11-66070590-A-C is Benign according to our data. Variant chr11-66070590-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211811.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PACS1	NM_018026.4	c.104A>C	p.Gln35Pro	missense_variant	1/24	ENST00000320580.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PACS1	ENST00000320580.9	c.104A>C	p.Gln35Pro	missense_variant	1/24	1	NM_018026.4	P2
PACS1	ENST00000527224.1	n.228A>C		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.000477 AC: 72 AN: 150966 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000679

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000586 AC: 52 AN: 88800 Hom.: 0 AF XY: 0.000607 AC XY: 31 AN XY: 51032

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.000166

Gnomad EAS exome AF: 0.00143

Gnomad SAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000247 AC: 308 AN: 1246054 Hom.: 1 Cov.: 31 AF XY: 0.000278 AC XY: 171 AN XY: 615294

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000407

Gnomad4 ASJ exome AF: 0.0000467

Gnomad4 EAS exome AF: 0.000777

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000477 AC: 72 AN: 151072 Hom.: 1 Cov.: 32 AF XY: 0.000434 AC XY: 32 AN XY: 73790

Gnomad4 AFR AF: 0.000677

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00334

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00143

Bravo AF: 0.000427

ExAC AF: 0.000232 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 11, 2014

- -

PACS1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2021

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.4
DANN	Benign	0.25
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.054
Sift	Benign	0.36	T
Sift4G	Benign	0.27	T
Vest4		0.23
MVP		0.33
MPC		1.4
ClinPred		0.010	T
Varity_R		0.15
gMVP		0.098

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: rs369233658; hg19: chr11-65838061; COSMIC: COSV57697237; COSMIC: COSV57697237;