rs3088241

Variant names:

• chr11-125893851-C-G
• rs3088241
• NM_031307.4:c.1380G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-125893851-C-G
• chr11-125893851-C-T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: -0.00800
• Publications: 28 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• hydrolethalus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS3	NM_031307.4	MANE Select	c.1380G>C	p.Glu460Asp	missense	Exon 4 of 4	NP_112597.4
	HYLS1	NM_001134793.2	MANE Select	c.-26+2379C>G		intron	N/A	NP_001128265.1
	PUS3	NM_001441237.1		c.1380G>C	p.Glu460Asp	missense	Exon 5 of 5	NP_001428166.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS3	ENST00000227474.8	TSL:1 MANE Select	c.1380G>C	p.Glu460Asp	missense	Exon 4 of 4	ENSP00000227474.3
	PUS3	ENST00000530811.5	TSL:1	c.1380G>C	p.Glu460Asp	missense	Exon 3 of 3	ENSP00000432386.1
	HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.-26+2379C>G		intron	N/A	ENSP00000414884.2

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

GnomAD2 exomes AF: 0.492 AC: 123742 AN: 251382 AF XY: 0.496

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 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

African (AFR) AF: 0.395 AC: 13217 AN: 33472

American (AMR) AF: 0.456 AC: 20384 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13604 AN: 26130

East Asian (EAS) AF: 0.541 AC: 21461 AN: 39696

South Asian (SAS) AF: 0.518 AC: 44661 AN: 86254

European-Finnish (FIN) AF: 0.512 AC: 27339 AN: 53418

Middle Eastern (MID) AF: 0.429 AC: 2475 AN: 5766

European-Non Finnish (NFE) AF: 0.504 AC: 560128 AN: 1111780

Other (OTH) AF: 0.493 AC: 29754 AN: 60390

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

African (AFR) AF: 0.401 AC: 16596 AN: 41398

American (AMR) AF: 0.454 AC: 6938 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1815 AN: 3464

East Asian (EAS) AF: 0.531 AC: 2740 AN: 5160

South Asian (SAS) AF: 0.497 AC: 2384 AN: 4796

European-Finnish (FIN) AF: 0.509 AC: 5351 AN: 10514

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.499 AC: 33927 AN: 67934

Other (OTH) AF: 0.441 AC: 930 AN: 2110

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.0080
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.041
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.0030	B
Vest4		0.032
MutPred		0.092		Loss of helix (P = 0.0196)
MPC		0.084
ClinPred		0.0072	T
GERP RS		-2.1
Varity_R		0.036
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

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