rs104894232

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001134793.2(HYLS1):c.632A>G(p.Asp211Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000621 in 1,614,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

HYLS1
NM_001134793.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.80

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-125900000-A-G is Pathogenic according to our data. Variant chr11-125900000-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-125900000-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.06503627). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYLS1	NM_001134793.2 link	c.632A>G	p.Asp211Gly	missense_variant	Exon 3 of 3	ENST00000425380.7	NP_001128265.1	Q96M11A0A024R3K0
PUS3	NM_031307.4 link	c.-47+3170T>C		intron_variant	Intron 1 of 3	ENST00000227474.8	NP_112597.4	Q9BZE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYLS1	ENST00000425380.7 link	c.632A>G	p.Asp211Gly	missense_variant	Exon 3 of 3	3	NM_001134793.2	ENSP00000414884.2		Q96M11
PUS3	ENST00000227474.8 link	c.-47+3170T>C		intron_variant	Intron 1 of 3	1	NM_031307.4	ENSP00000227474.3		Q9BZE2

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

144

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00110

AC:

277

AN:

251480

Hom.:

AF XY:

0.00107

AC XY:

146

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00919

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000588

AC:

859

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

410

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00857

Gnomad4 NFE exome

AF:

0.000319

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000945

AC:

144

AN:

152346

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00110

AC:

133

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hydrolethalus syndrome 1

Pathogenic:5

Dec 27, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001134793.1(HYLS1):c.632A>G(D211G) is classified as pathogenic in the context of hydrolethalus syndrome. Sources cited for classification include the following: PMID 15843405, 18648327, 19400947 and 19656802. Classification of NM_001134793.1(HYLS1):c.632A>G(D211G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jan 27, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632A>G (p.Asp211Gly) missense variant in the HYLS1 gene has been previously reported in 24 affected individuals with autosomal recessive Hydrolethalus syndrome from 16 families in Finland; this variant was shown to co-segregate with disease in these families (Mee et al., 2005). The residue encoded by this variant is positioned at a protease cleavage site, which is lost upon substitution to glycine (Paetau et al., 2008). Functional studies show this variant affects the subcellular localization, sequestering the protein primarily to the nucleus as opposed to the cytoplasm (Mee et al., 2005). This c.632A>G has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP] , 1000 Genomes, and ExAC). Multiple lines of computational evidence suggest a deleterious effect. Therefore, this collective evidence supports the classification of the c.632A>G (p.Asp211Gly) as a recessive Pathogenic variant for Hydrolethalus syndrome. -

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PS3, PM1, PS4_Moderate, PP1, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

not provided

Pathogenic:3

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 211 of the HYLS1 protein (p.Asp211Gly). This variant is present in population databases (rs104894232, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with hydrolethalus syndrome (PMID: 15843405, 18648327). It is commonly reported in individuals of Finnish ancestry (PMID: 15843405, 18648327). ClinVar contains an entry for this variant (Variation ID: 1143). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HYLS1 function (PMID: 15843405). For these reasons, this variant has been classified as Pathogenic. -

Apr 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on activation of Hedgehog signaling (Chen et al., 2021); This variant is associated with the following publications: (PMID: 32371413, 34212369, 31589614, 19656802, 35611473, 15843405, 2074561, Morgan[Computational]2017, 34831381, 18648327, 19400947, 34162535) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HYLS1 p.D211G variant is reported to be a Finnish founder mutation and has been reported as a homozygous variant in 41 Finnish cases of hydrolethalus syndrome (HLS) (Mee_2005_PMID:15843405; Paetau_2008_PMID:18648327). The variant was identified in dbSNP (ID: rs104894232) and ClinVar (classified as pathogenic by Invitae, Knight Diagnostic Laboratories, Illumina and BGI Genomics). The variant was identified in control databases in 335 of 282870 chromosomes at a frequency of 0.001184 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 241 of 25120 chromosomes (freq: 0.009594), Other in 12 of 7228 chromosomes (freq: 0.00166), European (non-Finnish) in 79 of 129190 chromosomes (freq: 0.000612), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and African in 2 of 24964 chromosomes (freq: 0.00008), but was not observed in the Latino, East Asian, or South Asian populations. The p.D211 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, functional analysis has demonstrated that the p.D211G variant causes mislocalization of the HYLS1 protein to the nucleaus instead of the cytoplasm (Mee_2005_PMID:15843405). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Hydrolethalus syndrome

Pathogenic:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_145014.2:c.632A>G in the HYLS1 gene has an allele frequency of 0.01 in European (Finnish) subpopulation in the gnomAD database. The p.Asp211Gly (NM_145014.2:c.632A>G) variant has been observed in individuals with hydrolethalus syndrome and it has been reported to be a founder mutation in the Finnish population (PMID: 15843405; 18648327). Experimental studies have shown that this missense change causes mislocalization of the HYLS1 protein to the nucleus (PMID: 15843405). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3. -

Feb 24, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D;D

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

.;.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.96

MVP

0.83

MPC

0.71

ClinPred

0.16

GERP RS

5.5

Varity_R

0.90

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over