chr11-66216738-C-T

Variant names:

• chr11-66216738-C-T
• rs1554990856
• NM_018026.4:c.941C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.43

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]

ACMG classification

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
PACS1	NM_018026.4	c.941C>T	p.Thr314Ile	missense_variant	Exon 7 of 24	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.647C>T	p.Thr216Ile	missense_variant	Exon 7 of 24		XP_011543464.2
PACS1	XM_011545164.3	c.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
PACS1	ENST00000320580.9	c.941C>T	p.Thr314Ile	missense_variant	Exon 7 of 24	1	NM_018026.4	ENSP00000316454.4
PACS1	ENST00000524784.1	n.113C>T		non_coding_transcript_exon_variant	Exon 2 of 6	4		ENSP00000435037.1
PACS1	ENST00000527224.1	n.1065C>T		non_coding_transcript_exon_variant	Exon 7 of 7	2
PACS1	ENST00000531298.5	n.200C>T		non_coding_transcript_exon_variant	Exon 3 of 5	4		ENSP00000437274.1

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

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

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

- -

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

Other links and lift over

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