rs3088241

chr11-125893851-C-Gchr11-125893851-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031307.4(PUS3):c.1380G>C(p.Glu460Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,484 control chromosomes in the GnomAD database, including 201,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (16801 hom., cov: 31)
  • Exomes 𝑓: 0.50 (184569 hom.)
• Consequence: PUS3 NM_031307.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00800

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.976661E-5).
• BP6: Variant 11-125893851-C-G is Benign according to our data. Variant chr11-125893851-C-G is described in ClinVar as [Benign]. Clinvar id is 1168501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUS3	NM_031307.4	c.1380G>C	p.Glu460Asp	missense_variant	4/4	ENST00000227474.8
HYLS1	NM_001134793.2	c.-26+2379C>G		intron_variant		ENST00000425380.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUS3	ENST00000227474.8	c.1380G>C	p.Glu460Asp	missense_variant	4/4	1	NM_031307.4	P1
HYLS1	ENST00000425380.7	c.-26+2379C>G		intron_variant		3	NM_001134793.2	P1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71155 AN: 151736 Hom.: 16794 Cov.: 31

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.492 AC: 123742 AN: 251382 Hom.: 30695 AF XY: 0.496 AC XY: 67328 AN XY: 135874

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.536

Gnomad SAS exome AF: 0.517

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.502 AC: 733023 AN: 1461630 Hom.: 184569 Cov.: 39 AF XY: 0.502 AC XY: 365269 AN XY: 727126

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.541

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.493

GnomAD4 genome AF: 0.469 AC: 71191 AN: 151854 Hom.: 16801 Cov.: 31 AF XY: 0.470 AC XY: 34862 AN XY: 74174

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.497

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.441

Alfa AF: 0.492 Hom.: 13827

Bravo AF: 0.462

TwinsUK AF: 0.492 AC: 1826

ALSPAC AF: 0.517 AC: 1992

ESP6500AA AF: 0.404 AC: 1779

ESP6500EA AF: 0.499 AC: 4289

ExAC AF: 0.493 AC: 59852

Asia WGS AF: 0.503 AC: 1752 AN: 3478

EpiCase AF: 0.484

EpiControl AF: 0.480

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0085	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.00010	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	N;N;.
REVEL	Benign	0.041
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.032
MutPred		0.092		Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);.;
MPC		0.084
ClinPred		0.0072	T
GERP RS		-2.1
Varity_R		0.036
gMVP		0.12

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: rs3088241; hg19: chr11-125763746; COSMIC: COSV57104607; COSMIC: COSV57104607;