chr11-66070563-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_018026.4(PACS1):c.77C>T(p.Ala26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000388 in 1,469,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PACS1
NM_018026.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.43

Publications

0 publications found

Variant links:

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

PACS1 links:

ENSG00000255038 (HGNC:):

ENSG00000255038 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08406377).

BP6

Variant 11-66070563-C-T is Benign according to our data. Variant chr11-66070563-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2457220.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 13 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.77C>T	p.Ala26Val	missense	Exon 1 of 24	NP_060496.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PACS1	ENST00000320580.9	TSL:1 MANE Select	c.77C>T	p.Ala26Val	missense	Exon 1 of 24	ENSP00000316454.4	Q6VY07-1
PACS1	ENST00000527224.1	TSL:2	n.201C>T		non_coding_transcript_exon	Exon 1 of 7
ENSG00000255038	ENST00000830157.1		n.29+467G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

151552

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000267

AC:

AN:

74768

AF XY:

0.0000233

show subpopulations

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:

0.0000753

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000334

AC:

AN:

1317528

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

649432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26604

American (AMR)

AF:

0.00

AC:

AN:

26728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22728

East Asian (EAS)

AF:

0.00

AC:

AN:

28190

South Asian (SAS)

AF:

0.00

AC:

AN:

72086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3946

European-Non Finnish (NFE)

AF:

0.0000400

AC:

AN:

1049314

Other (OTH)

AF:

0.0000366

AC:

AN:

54616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000858

AC:

AN:

151552

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41346

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000192

AC:

AN:

67758

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000949

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

1.4

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.20

REVEL

Benign

0.035

Sift

Pathogenic

0.0

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.16

MutPred

0.25

Gain of sheet (P = 0.0344)

MVP

0.14

MPC

1.2

ClinPred

0.25

GERP RS

2.9

PromoterAI

-0.057

Neutral

(source)

Varity_R

0.24

gMVP

0.086

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over