11-112260411-T-C

Position:

• chr11-112260411-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145024.1(PLET1):​c.179A>G​(p.Tyr60Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,398,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PLET1 NM_001145024.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

PLET1 (HGNC:30053): (placenta expressed transcript 1) Predicted to be involved in negative regulation of cell-matrix adhesion; positive regulation of cell migration; and wound healing, spreading of epidermal cells. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in apical plasma membrane and external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PTS (HGNC:9689): (6-pyruvoyltetrahydropterin synthase) The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

ENSG00000268472 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLET1	NM_001145024.1	c.179A>G	p.Tyr60Cys	missense_variant	1/4	ENST00000338832.4	NP_001138496.1
LOC100132686	NR_133566.1	n.147T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLET1	ENST00000338832.4	c.179A>G	p.Tyr60Cys	missense_variant	1/4	5	NM_001145024.1	ENSP00000341412.2
PTS	ENST00000531673.5	n.*364-9146T>C		intron_variant		1		ENSP00000433469.1
ENSG00000268472	ENST00000595053.2	n.147T>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1398872 Hom.: 0 Cov.: 30 AF XY: 0.0000232 AC XY: 16 AN XY: 689968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000868

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2023

The c.179A>G (p.Y60C) alteration is located in exon 1 (coding exon 1) of the PLET1 gene. This alteration results from a A to G substitution at nucleotide position 179, causing the tyrosine (Y) at amino acid position 60 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.97	L
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.67		Loss of phosphorylation at Y60 (P = 0.079);
MVP		0.43
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.74
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1270283589; hg19: chr11-112131134;