rs9894254

Positions:

chr17-80210880-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000199.5(SGSH):c.1081G>A(p.Val361Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,612,936 control chromosomes in the GnomAD database, including 2,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 621 hom., cov: 33)

Exomes 𝑓: 0.049 ( 2016 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

SGSH links:

SGSH (HGNC:):

SGSH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019078851).

BP6

Variant 17-80210880-C-T is Benign according to our data. Variant chr17-80210880-C-T is described in ClinVar as [Benign]. Clinvar id is 92607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210880-C-T is described in Lovd as [Benign]. Variant chr17-80210880-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5 linkuse as main transcript	c.1081G>A	p.Val361Ile	missense_variant	8/8	ENST00000326317.11	NP_000190.1	P51688

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 linkuse as main transcript	c.1081G>A	p.Val361Ile	missense_variant	8/8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.0754

AC:

11470

AN:

152152

Hom.:

620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0756

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0645

GnomAD3 exomes

AF:

0.0501

AC:

12507

AN:

249790

Hom.:

460

AF XY:

0.0488

AC XY:

6596

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.0471

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0316

Gnomad FIN exome

AF:

0.0729

Gnomad NFE exome

AF:

0.0507

Gnomad OTH exome

AF:

0.0530

GnomAD4 exome

AF:

0.0486

AC:

70977

AN:

1460668

Hom.:

2016

Cov.:

AF XY:

0.0477

AC XY:

34693

AN XY:

726580

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.0328

Gnomad4 ASJ exome

AF:

0.0480

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0328

Gnomad4 FIN exome

AF:

0.0731

Gnomad4 NFE exome

AF:

0.0475

Gnomad4 OTH exome

AF:

0.0528

GnomAD4 genome

AF:

0.0754

AC:

11487

AN:

152268

Hom.:

621

Cov.:

AF XY:

0.0736

AC XY:

5483

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.0440

Gnomad4 ASJ

AF:

0.0499

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0263

Gnomad4 FIN

AF:

0.0756

Gnomad4 NFE

AF:

0.0478

Gnomad4 OTH

AF:

0.0639

Alfa

AF:

0.0510

Hom.:

594

Bravo

AF:

0.0771

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.143

AC:

629

ESP6500EA

AF:

0.0508

AC:

437

ExAC

AF:

0.0533

AC:

6473

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0463

EpiControl

AF:

0.0491

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Benign:6

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	Variant summary: The SGSH c.1081G>A (p.Val361Ile) variant causes a missense change involving a conserved nucleotide with 3/3 in silico tools (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value, respectively) predict a benign outcome for this variant. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 6457/120406 (1/18, 258 homozygoes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SGSH variant of 1/309 (0.0032275), suggesting this variant is likely a benign polymorphism. A reputable clinical laboratory cites the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.050

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.66

REVEL

Benign

0.20

Sift

Benign

0.24

Sift4G

Benign

0.19

Polyphen

0.065

Vest4

0.11

MPC

0.20

ClinPred

0.0091

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.65

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