11-66070587-C-CGCA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_018026.4(PACS1):c.119_121dup(p.Gln40dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,493,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PACS1 NM_018026.4 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0640

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 11-66070587-C-CGCA is Benign according to our data. Variant chr11-66070587-C-CGCA is described in ClinVar as [Benign]. Clinvar id is 1744643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PACS1	NM_018026.4	c.119_121dup	p.Gln40dup	inframe_insertion	1/24	ENST00000320580.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PACS1	ENST00000320580.9	c.119_121dup	p.Gln40dup	inframe_insertion	1/24	1	NM_018026.4	P2
PACS1	ENST00000527224.1	n.243_245dup		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151402 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000886

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 11 AN: 91850 Hom.: 0 AF XY: 0.000153 AC XY: 8 AN XY: 52414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000232

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 180 AN: 1342440 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 97 AN XY: 663110

Gnomad4 AFR exome AF: 0.000221

Gnomad4 AMR exome AF: 0.0000632

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000233

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.000176

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.000197

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151402 Hom.: 0 Cov.: 32 AF XY: 0.0000947 AC XY: 7 AN XY: 73908

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.0000886

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749515977; hg19: chr11-65838058;