rs9894254

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V361V) has been classified as Likely 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:

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000199.5

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 rank	MANE	Protein	UniProt
SGSH	NM_000199.5 link	c.1081G>A	p.Val361Ile	missense_variant	Exon 8 of 8	ENST00000326317.11	NP_000190.1	P51688

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 link	c.1081G>A	p.Val361Ile	missense_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.0501

AC:

12507

AN:

249790

AF XY:

0.0488

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 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

AC:

5121

AN:

33478

Gnomad4 AMR exome

AF:

0.0328

AC:

1466

AN:

44722

Gnomad4 ASJ exome

AF:

0.0480

AC:

1255

AN:

26134

Gnomad4 EAS exome

AF:

0.000151

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0328

AC:

2827

AN:

86254

Gnomad4 FIN exome

AF:

0.0731

AC:

3822

AN:

52276

Gnomad4 NFE exome

AF:

0.0475

AC:

52852

AN:

1111964

Gnomad4 Remaining exome

AF:

0.0528

AC:

3187

AN:

60372

Heterozygous variant carriers

4470

8940

13409

17879

22349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

2014

4028

6042

8056

10070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.151013

AN:

0.151013

Gnomad4 AMR

AF:

0.0440

AC:

0.0439582

AN:

0.0439582

Gnomad4 ASJ

AF:

0.0499

AC:

0.0498559

AN:

0.0498559

Gnomad4 EAS

AF:

0.000579

AC:

0.000579151

AN:

0.000579151

Gnomad4 SAS

AF:

0.0263

AC:

0.0262831

AN:

0.0262831

Gnomad4 FIN

AF:

0.0756

AC:

0.0755518

AN:

0.0755518

Gnomad4 NFE

AF:

0.0478

AC:

0.0478473

AN:

0.0478473

Gnomad4 OTH

AF:

0.0639

AC:

0.06386

AN:

0.06386

Heterozygous variant carriers

549

1098

1648

2197

2746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0565

Hom.:

1108

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Jun 05, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 15, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Mutation Taster

=86/14

polymorphism (auto)

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