chr11-66216738-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_018026.4(PACS1):​c.941C>T​(p.Thr314Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,766 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T314S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PACS1
NM_018026.4 missense

Scores

5
14

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.43
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11475539).
BP6
Variant 11-66216738-C-T is Benign according to our data. Variant chr11-66216738-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436133.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PACS1NM_018026.4 linkc.941C>T p.Thr314Ile missense_variant Exon 7 of 24 ENST00000320580.9 NP_060496.2 Q6VY07-1A0A024R5H6
PACS1XM_011545162.2 linkc.647C>T p.Thr216Ile missense_variant Exon 7 of 24 XP_011543464.2
PACS1XM_011545164.3 linkc.602C>T p.Thr201Ile missense_variant Exon 7 of 24 XP_011543466.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PACS1ENST00000320580.9 linkc.941C>T p.Thr314Ile missense_variant Exon 7 of 24 1 NM_018026.4 ENSP00000316454.4 Q6VY07-1
PACS1ENST00000524784.1 linkn.113C>T non_coding_transcript_exon_variant Exon 2 of 6 4 ENSP00000435037.1 H0YE62
PACS1ENST00000527224.1 linkn.1065C>T non_coding_transcript_exon_variant Exon 7 of 7 2
PACS1ENST00000531298.5 linkn.200C>T non_coding_transcript_exon_variant Exon 3 of 5 4 ENSP00000437274.1 H0YF56

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461766
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 03, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.080
T
Eigen
Benign
-0.11
Eigen_PC
Benign
0.087
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-2.4
N
REVEL
Benign
0.055
Sift
Benign
0.21
T
Sift4G
Benign
0.088
T
Polyphen
0.089
B
Vest4
0.16
MutPred
0.21
Loss of phosphorylation at T314 (P = 0.0059);
MVP
0.15
MPC
0.98
ClinPred
0.42
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554990856; hg19: chr11-65984209; COSMIC: COSV104629621; COSMIC: COSV104629621; API