Genetic Variant HYLS1:p.Asp211Gly (chr11-125900000-AC-GA) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is . The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_001134793.2(HYLS1):c.632_633delACinsGA(p.Asp211Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

HYLS1
NM_001134793.2 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.80

Publications

0 publications found

Variant links:

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]

HYLS1 links:

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: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

PUS3 links:

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new If you want to explore the variant's impact on the transcript NM_001134793.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PS1

Transcript NM_001134793.2 (HYLS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYLS1	NM_001134793.2	MANE Select	c.632_633delACinsGA	p.Asp211Gly	missense	N/A	NP_001128265.1	Q96M11
PUS3	NM_031307.4	MANE Select	c.-47+3169_-47+3170delGTinsTC		intron	N/A	NP_112597.4
HYLS1	NM_001377269.1		c.632_633delACinsGA	p.Asp211Gly	missense	N/A	NP_001364198.1	Q96M11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.632_633delACinsGA	p.Asp211Gly	missense	N/A	ENSP00000414884.2	Q96M11
PUS3	ENST00000227474.8	TSL:1 MANE Select	c.-47+3169_-47+3170delGTinsTC		intron	N/A	ENSP00000227474.3	Q9BZE2
HYLS1	ENST00000356438.7	TSL:5	c.632_633delACinsGA	p.Asp211Gly	missense	N/A	ENSP00000348815.3	Q96M11

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over