11-66114287-G-A

Variant names:

• chr11-66114287-G-A
• rs7932272
• NM_018026.4:c.356+43445G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018026.4(PACS1):​c.356+43445G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 151,910 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.057 (384 hom., cov: 28)
• Consequence: PACS1 NM_018026.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.809
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Schuurs-Hoeijmakers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACS1	NM_018026.4	c.356+43445G>A		intron_variant	Intron 1 of 23	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.62+13413G>A		intron_variant	Intron 1 of 23		XP_011543464.2
PACS1	XM_011545164.3	c.17+30057G>A		intron_variant	Intron 1 of 23		XP_011543466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACS1	ENST00000320580.9	c.356+43445G>A		intron_variant	Intron 1 of 23	1	NM_018026.4	ENSP00000316454.4
PACS1	ENST00000527380.1	c.62+13413G>A		intron_variant	Intron 1 of 4	4		ENSP00000432639.1
PACS1	ENST00000533756.5	c.1-6734G>A		intron_variant	Intron 1 of 4	4		ENSP00000437150.1
PACS1	ENST00000527224.1	n.480+43445G>A		intron_variant	Intron 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8620 AN: 151792 Hom.: 385 Cov.: 28

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0769

Gnomad OTH AF: 0.0470

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0567 AC: 8615 AN: 151910 Hom.: 384 Cov.: 28 AF XY: 0.0602 AC XY: 4470 AN XY: 74204

African (AFR) AF: 0.0139 AC: 576 AN: 41448

American (AMR) AF: 0.0311 AC: 474 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0382 AC: 184 AN: 4814

European-Finnish (FIN) AF: 0.176 AC: 1848 AN: 10490

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0769 AC: 5223 AN: 67946

Other (OTH) AF: 0.0465 AC: 98 AN: 2108

Alfa AF: 0.0671 Hom.: 42

Bravo AF: 0.0435

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.46
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7932272; hg19: chr11-65881758;