8-56166670-T-TA

Position:

• chr8-56166670-T-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002655.3(PLAG1):​c.1075_1076insT​(p.Tyr359LeufsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLAG1 NM_002655.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.94

Genes affected

PLAG1 (HGNC:9045): (PLAG1 zinc finger) Pleomorphic adenoma gene 1 encodes a zinc finger protein with 2 putative nuclear localization signals. PLAG1, which is developmentally regulated, has been shown to be consistently rearranged in pleomorphic adenomas of the salivary glands. PLAG1 is activated by the reciprocal chromosomal translocations involving 8q12 in a subset of salivary gland pleomorphic adenomas. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.285 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-56166670-T-TA is Pathogenic according to our data. Variant chr8-56166670-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2637241.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAG1	NM_002655.3	c.1075_1076insT	p.Tyr359LeufsTer23	frameshift_variant	5/5	ENST00000316981.8	NP_002646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAG1	ENST00000316981.8	c.1075_1076insT	p.Tyr359LeufsTer23	frameshift_variant	5/5	1	NM_002655.3	ENSP00000325546	P1
PLAG1	ENST00000429357.2	c.1075_1076insT	p.Tyr359LeufsTer23	frameshift_variant	4/4	1		ENSP00000416537	P1
PLAG1	ENST00000522009.1	n.1526_1527insT		non_coding_transcript_exon_variant	3/3	1
PLAG1	ENST00000423799.6	c.829_830insT	p.Tyr277LeufsTer23	frameshift_variant	3/3	2		ENSP00000404067

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PLAG1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2022

The PLAG1 c.1075dupT variant is predicted to result in a frameshift and premature protein termination (p.Tyr359Leufs*23). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although this protein truncating variant is located within the last exon (which could indicate that the non-sense mediated decay may not take place and protein product may still be present) this variant shortens the protein product substantially by 118 amino acid residues. In addition pathogenic protein truncating variants were observed downstream as well as upstream of this variant (Habib et al. 2018. PubMed ID: 28796236). Frameshift variants in PLAG1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-57079229;