chr8-56166670-T-TA

Variant names:

• chr8-56166670-T-TA
• NM_002655.3:c.1075dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002655.3(PLAG1):​c.1075dupT​(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
• Publications: 0 publications found

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]

PLAG1 Gene-Disease associations (from GenCC):

• silver-russell syndrome 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 3 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 VariationId is 2637241.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002655.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAG1	NM_002655.3	MANE Select	c.1075dupT	p.Tyr359LeufsTer23	frameshift	Exon 5 of 5	NP_002646.2	Q6DJT9-1
	PLAG1	NM_001114634.2		c.1075dupT	p.Tyr359LeufsTer23	frameshift	Exon 4 of 4	NP_001108106.1	Q6DJT9-1
	PLAG1	NM_001114635.2		c.829dupT	p.Tyr277LeufsTer23	frameshift	Exon 3 of 3	NP_001108107.1	Q6DJT9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAG1	ENST00000316981.8	TSL:1 MANE Select	c.1075dupT	p.Tyr359LeufsTer23	frameshift	Exon 5 of 5	ENSP00000325546.3	Q6DJT9-1
	PLAG1	ENST00000429357.2	TSL:1	c.1075dupT	p.Tyr359LeufsTer23	frameshift	Exon 4 of 4	ENSP00000416537.2	Q6DJT9-1
	PLAG1	ENST00000522009.1	TSL:1	n.1526dupT		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	PLAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

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

Other links and lift over

hg19: chr8-57079229;