chr11-66070621-G-T

Variant names:

• chr11-66070621-G-T
• rs778693310
• NM_018026.4:c.135G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_018026.4(PACS1):​c.135G>T​(p.Pro45Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,542,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PACS1 NM_018026.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000255038 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-66070621-G-T is Benign according to our data. Variant chr11-66070621-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 211812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	NM_018026.4	MANE Select	c.135G>T	p.Pro45Pro	synonymous	Exon 1 of 24	NP_060496.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	ENST00000320580.9	TSL:1 MANE Select	c.135G>T	p.Pro45Pro	synonymous	Exon 1 of 24	ENSP00000316454.4
	PACS1	ENST00000527224.1	TSL:2	n.259G>T		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000255038	ENST00000830157.1		n.29+409C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000252 AC: 4 AN: 158822 AF XY: 0.0000333

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: 0.0000564

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000360 AC: 50 AN: 1390274 Hom.: 0 Cov.: 30 AF XY: 0.0000406 AC XY: 28 AN XY: 690360

African (AFR) AF: 0.00 AC: 0 AN: 28770

American (AMR) AF: 0.00 AC: 0 AN: 38858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24514

East Asian (EAS) AF: 0.00 AC: 0 AN: 33254

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36922

Middle Eastern (MID) AF: 0.000778 AC: 4 AN: 5140

European-Non Finnish (NFE) AF: 0.0000405 AC: 44 AN: 1085264

Other (OTH) AF: 0.0000173 AC: 1 AN: 57724

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74228

African (AFR) AF: 0.0000483 AC: 2 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 14, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		1.1
PromoterAI		0.033	Neutral

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: rs778693310; hg19: chr11-65838092;