rs1554990856

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-66216738-C-G
• chr11-66216738-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018026.4(PACS1):​c.941C>G​(p.Thr314Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T314I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PACS1 NM_018026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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=0.06406379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACS1	NM_018026.4	c.941C>G	p.Thr314Ser	missense_variant	Exon 7 of 24	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.647C>G	p.Thr216Ser	missense_variant	Exon 7 of 24		XP_011543464.2
PACS1	XM_011545164.3	c.602C>G	p.Thr201Ser	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>G	p.Thr314Ser	missense_variant	Exon 7 of 24	1	NM_018026.4	ENSP00000316454.4
PACS1	ENST00000524784.1	n.113C>G		non_coding_transcript_exon_variant	Exon 2 of 6	4		ENSP00000435037.1
PACS1	ENST00000527224.1	n.1065C>G		non_coding_transcript_exon_variant	Exon 7 of 7	2
PACS1	ENST00000531298.5	n.200C>G		non_coding_transcript_exon_variant	Exon 3 of 5	4		ENSP00000437274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Schuurs-Hoeijmakers syndrome Uncertain:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 314 of the PACS1 protein (p.Thr314Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PACS1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PACS1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.064
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.078
MutPred		0.19		Gain of methylation at K317 (P = 0.1096);
MVP		0.24
MPC		0.70
ClinPred		0.68	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.16

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;