11-125893822-C-G

Variant names:

• chr11-125893822-C-G
• rs750439608
• NM_031307.4:c.1409G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031307.4(PUS3):​c.1409G>C​(p.Arg470Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PUS3 NM_031307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14509541).

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.1409G>C	p.Arg470Thr	missense	Exon 4 of 4	NP_112597.4
	HYLS1	NM_001134793.2	MANE Select	c.-26+2350C>G		intron	N/A	NP_001128265.1	Q96M11
	PUS3	NM_001441237.1		c.1409G>C	p.Arg470Thr	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.1409G>C	p.Arg470Thr	missense	Exon 4 of 4	ENSP00000227474.3	Q9BZE2
	PUS3	ENST00000530811.5	TSL:1	c.1409G>C	p.Arg470Thr	missense	Exon 3 of 3	ENSP00000432386.1	Q9BZE2
	HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.-26+2350C>G		intron	N/A	ENSP00000414884.2	Q96M11

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251220 AF XY: 0.00000736

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.61
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.094
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		0.32	B
Vest4		0.43
MutPred		0.24		Gain of phosphorylation at R470 (P = 0.0374)
MVP		0.46
MPC		0.33
ClinPred		0.16	T
GERP RS		-0.81
Varity_R		0.069
gMVP		0.48
Mutation Taster		=96/4	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: rs750439608; hg19: chr11-125763717;