8-56166347-C-A

Variant names:

• chr8-56166347-C-A
• NM_002655.3:c.1399G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002655.3(PLAG1):​c.1399G>T​(p.Ala467Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLAG1 NM_002655.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033224225).

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.1399G>T	p.Ala467Ser	missense	Exon 5 of 5	NP_002646.2	Q6DJT9-1
	PLAG1	NM_001114634.2		c.1399G>T	p.Ala467Ser	missense	Exon 4 of 4	NP_001108106.1	Q6DJT9-1
	PLAG1	NM_001114635.2		c.1153G>T	p.Ala385Ser	missense	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.1399G>T	p.Ala467Ser	missense	Exon 5 of 5	ENSP00000325546.3	Q6DJT9-1
	PLAG1	ENST00000429357.2	TSL:1	c.1399G>T	p.Ala467Ser	missense	Exon 4 of 4	ENSP00000416537.2	Q6DJT9-1
	PLAG1	ENST00000522009.1	TSL:1	n.1850G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.56
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.063		Gain of glycosylation at A467 (P = 0.0258)
MVP		0.11
MPC		0.51
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.070
gMVP		0.27
Mutation Taster		=81/19	polymorphism

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: chr8-57078906;