rs58786455

chr17-80210845-C-T

Variant summary

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

The NM_000199.5(SGSH):c.1116G>A(p.Met372Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,882 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (130 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (123 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.75

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000199.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.004259199).
• BP6: Variant 17-80210845-C-T is Benign according to our data. Variant chr17-80210845-C-T is described in ClinVar as [Benign]. Clinvar id is 255513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210845-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGSH	NM_000199.5	c.1116G>A	p.Met372Ile	missense_variant	8/8	ENST00000326317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGSH	ENST00000326317.11	c.1116G>A	p.Met372Ile	missense_variant	8/8	1	NM_000199.5	P1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3421 AN: 152198 Hom.: 130 Cov.: 33

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00575

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00558 AC: 1400 AN: 250752 Hom.: 48 AF XY: 0.00407 AC XY: 552 AN XY: 135740

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00214 AC: 3135 AN: 1461566 Hom.: 123 Cov.: 34 AF XY: 0.00179 AC XY: 1305 AN XY: 727082

Gnomad4 AFR exome AF: 0.0790

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.00436

GnomAD4 genome AF: 0.0225 AC: 3421 AN: 152316 Hom.: 130 Cov.: 33 AF XY: 0.0220 AC XY: 1638 AN XY: 74482

Gnomad4 AFR AF: 0.0790

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00732 Hom.: 38

Bravo AF: 0.0246

ESP6500AA AF: 0.0735 AC: 324

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00702 AC: 852

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.26		Loss of disorder (P = 0.0623);
MVP		0.87
MPC		0.81
ClinPred		0.039	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.87

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

Other links and lift over

dbSNP: rs58786455; hg19: chr17-78184644;