rs755958473

Variant names:

• chr11-125893814-C-T
• rs755958473
• NM_031307.4:c.1417G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-125893814-C-T
• chr11-125893814-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_031307.4(PUS3):​c.1417G>A​(p.Val473Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000082 (1 hom.)
• Consequence: PUS3 NM_031307.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.524
• Publications: 0 publications found

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]

HYLS1 Gene-Disease associations (from GenCC):

• hydrolethalus syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hydrolethalus syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082045734).
• BP6: Variant 11-125893814-C-T is Benign according to our data. Variant chr11-125893814-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3390344.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031307.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS3	NM_031307.4	MANE Select	c.1417G>A	p.Val473Ile	missense	Exon 4 of 4	NP_112597.4
	HYLS1	NM_001134793.2	MANE Select	c.-26+2342C>T		intron	N/A	NP_001128265.1	Q96M11
	PUS3	NM_001441237.1		c.1417G>A	p.Val473Ile	missense	Exon 5 of 5	NP_001428166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS3	ENST00000227474.8	TSL:1 MANE Select	c.1417G>A	p.Val473Ile	missense	Exon 4 of 4	ENSP00000227474.3	Q9BZE2
	PUS3	ENST00000530811.5	TSL:1	c.1417G>A	p.Val473Ile	missense	Exon 3 of 3	ENSP00000432386.1	Q9BZE2
	HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.-26+2342C>T		intron	N/A	ENSP00000414884.2	Q96M11

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251082 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461520 Hom.: 1 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111790

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.52
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.072
Sift	Benign	0.38	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.13		Gain of sheet (P = 0.0827)
MVP		0.34
MPC		0.076
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.016
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs755958473; hg19: chr11-125763709;