chr17-80210802-C-T

Position:

chr17-80210802-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000199.5(SGSH):c.1159G>A(p.Val387Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,012 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 16 hom., cov: 33)

Exomes 𝑓: 0.011 ( 173 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.19

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=0.011575401).

BP6

Variant 17-80210802-C-T is Benign according to our data. Variant chr17-80210802-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210802-C-T is described in Lovd as [Likely_benign]. Variant chr17-80210802-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.01 (1525/152266) while in subpopulation SAS AF= 0.0337 (162/4814). AF 95% confidence interval is 0.0294. There are 16 homozygotes in gnomad4. There are 824 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5 linkuse as main transcript	c.1159G>A	p.Val387Met	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.1159G>A	p.Val387Met	missense_variant	8/8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1526

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0134

AC:

3362

AN:

251062

Hom.:

AF XY:

0.0151

AC XY:

2053

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.0236

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0111

AC:

16287

AN:

1461746

Hom.:

173

Cov.:

AF XY:

0.0122

AC XY:

8877

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00671

Gnomad4 ASJ exome

AF:

0.0264

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0335

Gnomad4 FIN exome

AF:

0.0216

Gnomad4 NFE exome

AF:

0.00927

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0100

AC:

1525

AN:

152266

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

824

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.0132

Gnomad4 ASJ

AF:

0.0314

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0337

Gnomad4 FIN

AF:

0.0210

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.00994

Hom.:

Bravo

AF:

0.00779

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.0132

AC:

1607

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 27, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SGSH: PM5, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 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. -

Mucopolysaccharidosis, MPS-III-A

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

0.056

Eigen_PC

Benign

-0.027

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

0.90

Vest4

0.12

MPC

0.50

ClinPred

0.030

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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