chr6-143941905-T-G

Position:

• chr6-143941905-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001317162.2(PLAGL1):​c.911A>C​(p.Asn304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,612,854 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: PLAGL1 NM_001317162.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.89

Genes affected

PLAGL1 (HGNC:9046): (PLAG1 like zinc finger 1) This gene encodes a C2H2 zinc finger protein that functions as a suppressor of cell growth. This gene is often deleted or methylated and silenced in cancer cells. In addition, overexpression of this gene during fetal development is thought to be the causal factor for transient neonatal diabetes mellitus (TNDM). Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding two different protein isoforms. The P1 downstream promoter of this gene is imprinted, with preferential expression from the paternal allele in many tissues. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031066835).
• BP6: Variant 6-143941905-T-G is Benign according to our data. Variant chr6-143941905-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 780121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 291 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAGL1	NM_001317162.2	c.911A>C	p.Asn304Thr	missense_variant	8/8	ENST00000674357.1	NP_001304091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAGL1	ENST00000674357.1	c.911A>C	p.Asn304Thr	missense_variant	8/8		NM_001317162.2	ENSP00000501459	P1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 151944 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00645

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00305

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00230 AC: 575 AN: 250312 Hom.: 1 AF XY: 0.00268 AC XY: 363 AN XY: 135278

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00661

Gnomad FIN exome AF: 0.000423

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00328 AC: 4795 AN: 1460792 Hom.: 13 Cov.: 32 AF XY: 0.00335 AC XY: 2436 AN XY: 726544

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00615

Gnomad4 FIN exome AF: 0.000640

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74334

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00687

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00305

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00151

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PLAGL1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0010
DANN	Benign	0.74
DEOGEN2	Benign	0.17	T;T;.;T;T;.;T;T;.;T;T;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	.;.;T;.;.;T;T;.;.;.;.;.;.;.
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N;N;.;N;N;.;N;N;.;N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;.;.;N;N;N;N;.;N;.;.;.;N;.
REVEL	Benign	0.023
Sift	Benign	0.13	T;.;.;T;T;T;T;.;T;.;.;.;T;.
Sift4G	Benign	0.29	T;.;T;T;T;T;T;.;T;T;.;.;T;T
Polyphen		0.0010	B;B;.;B;B;.;B;B;.;B;B;.;B;.
Vest4		0.071
MVP		0.27
MPC		0.36
ClinPred		0.0095	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.13

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: rs147054773; hg19: chr6-144263042;