8-56166374-G-T

Position:

• chr8-56166374-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002655.3(PLAG1):​c.1372C>A​(p.Pro458Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,613,370 control chromosomes in the GnomAD database, including 22,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1719 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21242 hom.)
• Consequence: PLAG1 NM_002655.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.8995695E-4).
• BP6: Variant 8-56166374-G-T is Benign according to our data. Variant chr8-56166374-G-T is described in ClinVar as [Benign]. Clinvar id is 1345016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAG1	NM_002655.3	c.1372C>A	p.Pro458Thr	missense_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.1372C>A	p.Pro458Thr	missense_variant	5/5	1	NM_002655.3	ENSP00000325546	P1
PLAG1	ENST00000429357.2	c.1372C>A	p.Pro458Thr	missense_variant	4/4	1		ENSP00000416537	P1
PLAG1	ENST00000522009.1	n.1823C>A		non_coding_transcript_exon_variant	3/3	1
PLAG1	ENST00000423799.6	c.1126C>A	p.Pro376Thr	missense_variant	3/3	2		ENSP00000404067

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20249 AN: 151992 Hom.: 1721 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0760

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.151 AC: 37814 AN: 251116 Hom.: 3323 AF XY: 0.157 AC XY: 21346 AN XY: 135726

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.0742

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.166 AC: 242560 AN: 1461260 Hom.: 21242 Cov.: 33 AF XY: 0.168 AC XY: 121984 AN XY: 726970

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.0761

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.133 AC: 20244 AN: 152110 Hom.: 1719 Cov.: 32 AF XY: 0.131 AC XY: 9758 AN XY: 74360

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0757

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.167

Alfa AF: 0.167 Hom.: 3680

Bravo AF: 0.130

TwinsUK AF: 0.189 AC: 699

ALSPAC AF: 0.173 AC: 668

ESP6500AA AF: 0.0395 AC: 174

ESP6500EA AF: 0.184 AC: 1586

ExAC AF: 0.150 AC: 18217

Asia WGS AF: 0.119 AC: 414 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.206

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.74
DEOGEN2	Benign	0.089	T;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	.;T;T
MetaRNN	Benign	0.00089	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.063	B;.;B
Vest4		0.057
MPC		0.64
ClinPred		0.0024	T
GERP RS		2.4
Varity_R		0.047
gMVP		0.35

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: rs35883156; hg19: chr8-57078933; COSMIC: COSV57613743;