NM_001134793.2:c.220_221delGA

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134793.2. 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
	HYLS1	NM_001134793.2	MANE Select	c.220_221delGA	p.Glu74LysfsTer2	frameshift	Exon 3 of 3	NP_001128265.1	Q96M11
	PUS3	NM_031307.4	MANE Select	c.-46-3258_-46-3257delCT		intron	N/A	NP_112597.4
	HYLS1	NM_001377269.1		c.220_221delGA	p.Glu74LysfsTer2	frameshift	Exon 2 of 2	NP_001364198.1	Q96M11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.220_221delGA	p.Glu74LysfsTer2	frameshift	Exon 3 of 3	ENSP00000414884.2	Q96M11
	PUS3	ENST00000227474.8	TSL:1 MANE Select	c.-46-3258_-46-3257delCT		intron	N/A	ENSP00000227474.3	Q9BZE2
	HYLS1	ENST00000356438.7	TSL:5	c.220_221delGA	p.Glu74LysfsTer2	frameshift	Exon 4 of 4	ENSP00000348815.3	Q96M11

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

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Hydrolethalus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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;