ENST00000529757.5:c.-22G>A

Variant names:

• chr11-66230544-G-A
• rs766187894
• ENST00000529757.5:c.-22G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000529757.5(PACS1):​c.-22G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,457,820 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (1 hom.)
• Consequence: PACS1 ENST00000529757.5 5_prime_UTR
• Scores: Splicing: ADA: 0.0002423
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.638
• Publications: 0 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-66230544-G-A is Benign according to our data. Variant chr11-66230544-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436131.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000529757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	NM_018026.4	MANE Select	c.1375-4G>A		splice_region intron	N/A	NP_060496.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	ENST00000529757.5	TSL:1	c.-22G>A		5_prime_UTR	Exon 1 of 13	ENSP00000432858.1	B4DF77
	PACS1	ENST00000320580.9	TSL:1 MANE Select	c.1375-4G>A		splice_region intron	N/A	ENSP00000316454.4	Q6VY07-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1457820 Hom.: 1 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725584

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1108314

Other (OTH) AF: 0.0000166 AC: 1 AN: 60244

GnomAD4 genome Cov.: 33

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.4
DANN	Benign	0.48
PhyloP100		0.64
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.0080
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766187894;

hg19: chr11-65998015;

COSMIC: COSV57699162;

COSMIC: COSV57699162;