11-66235408-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018026.4(PACS1):​c.2207+5G>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000687 in 1,455,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PACS1
NM_018026.4 splice_region, intron

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.03
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_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PACS1NM_018026.4 linkc.2207+5G>T splice_region_variant, intron_variant Intron 18 of 23 ENST00000320580.9 NP_060496.2 Q6VY07-1A0A024R5H6
PACS1XM_011545162.2 linkc.1913+5G>T splice_region_variant, intron_variant Intron 18 of 23 XP_011543464.2
PACS1XM_011545164.3 linkc.1868+5G>T splice_region_variant, intron_variant Intron 18 of 23 XP_011543466.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PACS1ENST00000320580.9 linkc.2207+5G>T splice_region_variant, intron_variant Intron 18 of 23 1 NM_018026.4 ENSP00000316454.4 Q6VY07-1
PACS1ENST00000529757.5 linkc.815+5G>T splice_region_variant, intron_variant Intron 7 of 12 1 ENSP00000432858.1 B4DF77
PACS1ENST00000529795.1 linkn.339G>T non_coding_transcript_exon_variant Exon 3 of 3 2
PACS1ENST00000676419.1 linkn.244+5G>T splice_region_variant, intron_variant Intron 3 of 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455888
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
724544
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.24
CADD
Pathogenic
26
DANN
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.29
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.20
Position offset: -8
DS_DL_spliceai
0.29
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66002879; API