rs9894254

Positions:

• chr17-80210880-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000326317.11(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 (★★). 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 ENST00000326317.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.23

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 ENST00000326317.11
• 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	c.1081G>A	p.Val361Ile	missense_variant	8/8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.1081G>A	p.Val361Ile	missense_variant	8/8	1	NM_000199.5	ENSP00000314606	P1

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11470 AN: 152152 Hom.: 620 Cov.: 33

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

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.: 35 AF XY: 0.0477 AC XY: 34693 AN XY: 726580

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.: 33 AF XY: 0.0736 AC XY: 5483 AN XY: 74448

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: 69 AN: 3478

EpiCase AF: 0.0463

EpiControl AF: 0.0491

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Benign:6

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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -
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. -
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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.050
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.2e-7	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.20
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.065	B
Vest4		0.11
MPC		0.20
ClinPred		0.0091	T
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

Other links and lift over

dbSNP: rs9894254; hg19: chr17-78184679;