rs1555102458

Variant names:

• chr11-125899586-TAG-T
• rs1555102458
• NM_001134793.2:c.220_221delGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001134793.2(HYLS1):​c.220_221delGA​(p.Glu74LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HYLS1 NM_001134793.2 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.372
• Publications: 0 publications found

Genes affected

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]

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]

PUS3 Gene-Disease associations (from GenCC):

• severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYLS1	NM_001134793.2	c.220_221delGA	p.Glu74LysfsTer2	frameshift_variant	Exon 3 of 3	ENST00000425380.7	NP_001128265.1
PUS3	NM_031307.4	c.-46-3258_-46-3257delCT		intron_variant	Intron 1 of 3	ENST00000227474.8	NP_112597.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYLS1	ENST00000425380.7	c.220_221delGA	p.Glu74LysfsTer2	frameshift_variant	Exon 3 of 3	3	NM_001134793.2	ENSP00000414884.2
PUS3	ENST00000227474.8	c.-46-3258_-46-3257delCT		intron_variant	Intron 1 of 3	1	NM_031307.4	ENSP00000227474.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hydrolethalus syndrome 1 Uncertain:1

Apr 03, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37

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: rs1555102458; hg19: chr11-125769481;