NM_018026.4:c.119_121delAGC

Variant names:

• chr11-66070587-CGCA-C
• rs749515977
• NM_018026.4:c.119_121delAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_018026.4(PACS1):​c.119_121delAGC​(p.Gln40del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,478,732 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: PACS1 NM_018026.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.163
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen

ENSG00000255038 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_018026.4
• BP6: Variant 11-66070587-CGCA-C is Benign according to our data. Variant chr11-66070587-CGCA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3060801.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018026.4. 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.119_121delAGC	p.Gln40del	disruptive_inframe_deletion	Exon 1 of 24	NP_060496.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	ENST00000320580.9	TSL:1 MANE Select	c.119_121delAGC	p.Gln40del	disruptive_inframe_deletion	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
	PACS1	ENST00000527224.1	TSL:2	n.243_245delAGC		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000255038	ENST00000830157.1		n.29+440_29+442delTGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000793 AC: 12 AN: 151372 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000963

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00390 AC: 358 AN: 91850 AF XY: 0.00366

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00648

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00698

GnomAD4 exome AF: 0.000613 AC: 813 AN: 1327254 Hom.: 0 AF XY: 0.000636 AC XY: 417 AN XY: 655152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000483 AC: 13 AN: 26904

American (AMR) AF: 0.00215 AC: 66 AN: 30740

Ashkenazi Jewish (ASJ) AF: 0.00251 AC: 58 AN: 23118

East Asian (EAS) AF: 0.00117 AC: 35 AN: 29814

South Asian (SAS) AF: 0.000832 AC: 61 AN: 73300

European-Finnish (FIN) AF: 0.000356 AC: 12 AN: 33722

Middle Eastern (MID) AF: 0.000712 AC: 3 AN: 4216

European-Non Finnish (NFE) AF: 0.000505 AC: 530 AN: 1050284

Other (OTH) AF: 0.000635 AC: 35 AN: 55156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000792 AC: 12 AN: 151478 Hom.: 0 Cov.: 32 AF XY: 0.0000946 AC XY: 7 AN XY: 74010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000656 AC: 1 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000963 AC: 1 AN: 10386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67672

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000766768), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00659 Hom.: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PACS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=91/9	polymorphism

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: rs749515977; hg19: chr11-65838058; COSMIC: COSV57696367; COSMIC: COSV57696367;