NM_018026.4:c.83C>G

Variant names:

• chr11-66070569-C-G
• rs763294619
• NM_018026.4:c.83C>G

Variant summary

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

The NM_018026.4(PACS1):​c.83C>G​(p.Ser28Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,478,700 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: PACS1 NM_018026.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.94
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008917958).
• BP6: Variant 11-66070569-C-G is Benign according to our data. Variant chr11-66070569-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211816.
• BS2: High AC in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	NM_018026.4	MANE Select	c.83C>G	p.Ser28Cys	missense	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.83C>G	p.Ser28Cys	missense	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
	PACS1	ENST00000527224.1	TSL:2	n.207C>G		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000255038	ENST00000830157.1		n.29+461G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000689 AC: 57 AN: 82706 AF XY: 0.000805

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: 0.0000337

Gnomad OTH exome AF: 0.000420

GnomAD4 exome AF: 0.000234 AC: 311 AN: 1327058 Hom.: 1 Cov.: 31 AF XY: 0.000316 AC XY: 207 AN XY: 654414

African (AFR) AF: 0.0000373 AC: 1 AN: 26842

American (AMR) AF: 0.00 AC: 0 AN: 28646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23118

East Asian (EAS) AF: 0.0000349 AC: 1 AN: 28666

South Asian (SAS) AF: 0.00336 AC: 247 AN: 73480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33638

Middle Eastern (MID) AF: 0.000743 AC: 3 AN: 4040

European-Non Finnish (NFE) AF: 0.0000437 AC: 46 AN: 1053504

Other (OTH) AF: 0.000236 AC: 13 AN: 55124

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151642 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74116

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67740

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000285 AC: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	PACS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.053
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.085	T
Polyphen		0.90	P
Vest4		0.24
MutPred		0.19		Loss of phosphorylation at S28 (P = 0.0174)
MVP		0.15
MPC		1.4
ClinPred		0.19	T
GERP RS		2.9
PromoterAI		-0.0060	Neutral
Varity_R		0.24
gMVP		0.17
Mutation Taster		=85/15	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: rs763294619; hg19: chr11-65838040;