6-143942014-G-A

Position:

• chr6-143942014-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001317162.2(PLAGL1):​c.802C>T​(p.Pro268Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLAGL1 NM_001317162.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0850

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061781466).
• BP6: Variant 6-143942014-G-A is Benign according to our data. Variant chr6-143942014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3214287.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAGL1	NM_001317162.2	c.802C>T	p.Pro268Ser	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.802C>T	p.Pro268Ser	missense_variant	8/8		NM_001317162.2	ENSP00000501459	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.015
DANN	Benign	0.47
DEOGEN2	Benign	0.20	T;T;.;T;T;.;T;T;.;T;T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.43	.;.;T;.;.;T;T;.;.;.;.;.;.;.
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	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	0.23	T
PROVEAN	Benign	-1.1	N;.;.;N;N;N;N;.;N;.;.;.;N;.
REVEL	Benign	0.024
Sift	Benign	0.58	T;.;.;T;T;T;T;.;T;.;.;.;T;.
Sift4G	Benign	0.42	T;.;T;T;T;T;T;.;T;T;.;.;T;T
Polyphen		0.0	B;B;.;B;B;.;B;B;.;B;B;.;B;.
Vest4		0.039
MutPred		0.33		Loss of catalytic residue at P267 (P = 0.0175);Loss of catalytic residue at P267 (P = 0.0175);.;Loss of catalytic residue at P267 (P = 0.0175);Loss of catalytic residue at P267 (P = 0.0175);.;Loss of catalytic residue at P267 (P = 0.0175);Loss of catalytic residue at P267 (P = 0.0175);.;Loss of catalytic residue at P267 (P = 0.0175);Loss of catalytic residue at P267 (P = 0.0175);.;Loss of catalytic residue at P267 (P = 0.0175);.;
MVP		0.17
MPC		0.35
ClinPred		0.042	T
GERP RS		-2.0
Varity_R		0.026
gMVP		0.16

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: rs1439245820; hg19: chr6-144263151;