rs75352646

Variant names:

• chr11-66070588-G-A
• rs75352646
• NM_018026.4:c.102G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018026.4(PACS1):​c.102G>A​(p.Pro34Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,443,956 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: PACS1 NM_018026.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0640
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-66070588-G-A is Benign according to our data. Variant chr11-66070588-G-A is described in ClinVar as Benign. ClinVar VariationId is 129868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.064 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2091/151352) while in subpopulation AFR AF = 0.0472 (1955/41418). AF 95% confidence interval is 0.0455. There are 38 homozygotes in GnomAd4. There are 978 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2091 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.102G>A	p.Pro34Pro	synonymous	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.102G>A	p.Pro34Pro	synonymous	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
	PACS1	ENST00000527224.1	TSL:2	n.226G>A		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000255038	ENST00000830157.1		n.29+442C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2087 AN: 151244 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00651

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00166 AC: 153 AN: 92258 AF XY: 0.00117

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000165

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00132 AC: 1712 AN: 1292604 Hom.: 30 Cov.: 31 AF XY: 0.00111 AC XY: 707 AN XY: 638002

African (AFR) AF: 0.0516 AC: 1369 AN: 26520

American (AMR) AF: 0.00286 AC: 81 AN: 28306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22316

East Asian (EAS) AF: 0.00 AC: 0 AN: 28976

South Asian (SAS) AF: 0.0000568 AC: 4 AN: 70406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32858

Middle Eastern (MID) AF: 0.00220 AC: 9 AN: 4082

European-Non Finnish (NFE) AF: 0.0000790 AC: 81 AN: 1025500

Other (OTH) AF: 0.00313 AC: 168 AN: 53640

GnomAD4 genome AF: 0.0138 AC: 2091 AN: 151352 Hom.: 38 Cov.: 32 AF XY: 0.0132 AC XY: 978 AN XY: 73952

African (AFR) AF: 0.0472 AC: 1955 AN: 41418

American (AMR) AF: 0.00651 AC: 99 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10392

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67632

Other (OTH) AF: 0.0105 AC: 22 AN: 2102

Alfa AF: 0.0130 Hom.: 3

Bravo AF: 0.0159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Schuurs-Hoeijmakers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.064
PromoterAI		0.051	Neutral
Mutation Taster		=100/0	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: rs75352646; hg19: chr11-65838059;