11-125893941-A-C

Position:

• chr11-125893941-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031307.4(PUS3):​c.1290T>G​(p.Phe430Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUS3 NM_031307.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

Genes affected

PUS3 (HGNC:25461): (pseudouridine synthase 3) The protein encoded by this gene catalyzes the formation of tRNA pseudouridine from tRNA uridine at position 39 in the anticodon stem and loop of transfer RNAs. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

HYLS1 (HGNC:26558): (HYLS1 centriolar and ciliogenesis associated) This gene encodes a protein localized to the cytoplasm. Mutations in this gene are associated with hydrolethalus syndrome. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2935491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUS3	NM_031307.4	c.1290T>G	p.Phe430Leu	missense_variant	4/4	ENST00000227474.8	NP_112597.4
HYLS1	NM_001134793.2	c.-26+2469A>C		intron_variant		ENST00000425380.7	NP_001128265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUS3	ENST00000227474.8	c.1290T>G	p.Phe430Leu	missense_variant	4/4	1	NM_031307.4	ENSP00000227474.3
HYLS1	ENST00000425380.7	c.-26+2469A>C		intron_variant		3	NM_001134793.2	ENSP00000414884.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.1290T>G (p.F430L) alteration is located in exon 4 (coding exon 3) of the PUS3 gene. This alteration results from a T to G substitution at nucleotide position 1290, causing the phenylalanine (F) at amino acid position 430 to be replaced by a leucine (L). 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	0.90
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.18
Sift	Benign	0.059	T;T;.
Sift4G	Benign	0.091	T;T;T
Polyphen		0.012	B;B;.
Vest4		0.41
MutPred		0.55		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;
MVP		0.66
MPC		0.11
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.28
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-125763836;