rs1114167318

Variant names:

• chr8-56166382-TG-T
• rs1114167318
• NM_002655.3:c.1363delC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002655.3(PLAG1):​c.1363delC​(p.Gln455SerfsTer16) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLAG1 NM_002655.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.62
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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 0.0931 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-56166382-TG-T is Pathogenic according to our data. Variant chr8-56166382-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253033.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAG1	NM_002655.3	c.1363delC	p.Gln455SerfsTer16	frameshift_variant	Exon 5 of 5	ENST00000316981.8	NP_002646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAG1	ENST00000316981.8	c.1363delC	p.Gln455SerfsTer16	frameshift_variant	Exon 5 of 5	1	NM_002655.3	ENSP00000325546.3
PLAG1	ENST00000429357.2	c.1363delC	p.Gln455SerfsTer16	frameshift_variant	Exon 4 of 4	1		ENSP00000416537.2
PLAG1	ENST00000522009.1	n.1814delC		non_coding_transcript_exon_variant	Exon 3 of 3	1
PLAG1	ENST00000423799.6	c.1117delC	p.Gln373SerfsTer16	frameshift_variant	Exon 3 of 3	2		ENSP00000404067.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Silver-russell syndrome 4 Pathogenic:1

Jun 15, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Silver-Russell syndrome 1 Pathogenic:1

-

Centre de Recherche Saint Antoine, Université Pierre et Marie Curie

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=5/195	disease causing (ClinVar)

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

dbSNP: rs1114167318; hg19: chr8-57078941;