rs3741370

Variant names:

• chr11-66222287-G-T
• rs3741370
• NM_018026.4:c.1293+1040G>T

Variant summary

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

The NM_018026.4(PACS1):​c.1293+1040G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,106 control chromosomes in the GnomAD database, including 1,412 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 0.11 (1412 hom., cov: 31)
• Consequence: PACS1 NM_018026.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACS1	NM_018026.4	c.1293+1040G>T		intron_variant	Intron 10 of 23	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.999+1040G>T		intron_variant	Intron 10 of 23		XP_011543464.2
PACS1	XM_011545164.3	c.954+1040G>T		intron_variant	Intron 10 of 23		XP_011543466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACS1	ENST00000320580.9	c.1293+1040G>T		intron_variant	Intron 10 of 23	1	NM_018026.4	ENSP00000316454.4

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17234 AN: 151988 Hom.: 1407 Cov.: 31

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.113 AC: 17245 AN: 152106 Hom.: 1412 Cov.: 31 AF XY: 0.119 AC XY: 8831 AN XY: 74342

African (AFR) AF: 0.0274 AC: 1136 AN: 41504

American (AMR) AF: 0.241 AC: 3680 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1084 AN: 5162

South Asian (SAS) AF: 0.0875 AC: 421 AN: 4812

European-Finnish (FIN) AF: 0.182 AC: 1922 AN: 10588

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8450 AN: 67978

Other (OTH) AF: 0.106 AC: 224 AN: 2108

Alfa AF: 0.124 Hom.: 903

Bravo AF: 0.116

Asia WGS AF: 0.163 AC: 565 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.34
PhyloP100		-2.1
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: rs3741370; hg19: chr11-65989758;