NM_018026.4:c.104A>C

Variant names:

• chr11-66070590-A-C
• rs369233658
• NM_018026.4:c.104A>C

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.104A>C​(p.Gln35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,397,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: PACS1 NM_018026.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.163
• Publications: 6 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=0.005846381).
• BP6: Variant 11-66070590-A-C is Benign according to our data. Variant chr11-66070590-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211811.
• BS2: High AC in GnomAd4 at 72 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.104A>C	p.Gln35Pro	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.104A>C	p.Gln35Pro	missense	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
	PACS1	ENST00000527224.1	TSL:2	n.228A>C		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000255038	ENST00000830157.1		n.29+440T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000477 AC: 72 AN: 150966 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000679

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000586 AC: 52 AN: 88800 AF XY: 0.000607

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.000166

Gnomad EAS exome AF: 0.00143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000247 AC: 308 AN: 1246054 Hom.: 1 Cov.: 31 AF XY: 0.000278 AC XY: 171 AN XY: 615294

African (AFR) AF: 0.000390 AC: 10 AN: 25626

American (AMR) AF: 0.000407 AC: 11 AN: 27046

Ashkenazi Jewish (ASJ) AF: 0.0000467 AC: 1 AN: 21404

East Asian (EAS) AF: 0.000777 AC: 22 AN: 28326

South Asian (SAS) AF: 0.00155 AC: 104 AN: 66938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.000106 AC: 105 AN: 989346

Other (OTH) AF: 0.00107 AC: 55 AN: 51618

GnomAD4 genome AF: 0.000477 AC: 72 AN: 151072 Hom.: 1 Cov.: 32 AF XY: 0.000434 AC XY: 32 AN XY: 73790

African (AFR) AF: 0.000677 AC: 28 AN: 41342

American (AMR) AF: 0.0000658 AC: 1 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00334 AC: 17 AN: 5090

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67556

Other (OTH) AF: 0.00143 AC: 3 AN: 2098

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000427

ExAC AF: 0.000232 AC: 24

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)
-	-	1	PACS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.4
DANN	Benign	0.25
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.16
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.054
Sift	Benign	0.36	T
Sift4G	Benign	0.27	T
Vest4		0.23
MVP		0.33
MPC		1.4
ClinPred		0.010	T
PromoterAI		-0.00040	Neutral
Varity_R		0.15
gMVP		0.098
Mutation Taster		=95/5	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: rs369233658; hg19: chr11-65838061; COSMIC: COSV57697237; COSMIC: COSV57697237;