rs9900509

Variant names:

• chr17-80217237-C-T
• rs9900509
• NM_000199.5:c.89-45G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000199.5(SGSH):​c.89-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 1,571,782 control chromosomes in the GnomAD database, including 4,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1883 hom., cov: 34)
  • Exomes 𝑓: 0.044 (2692 hom.)
• Consequence: SGSH NM_000199.5 intron
• Scores: Splicing: ADA: 0.00002686
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.197
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-80217237-C-T is Benign according to our data. Variant chr17-80217237-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5	c.89-45G>A		intron_variant	Intron 1 of 7	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.89-45G>A		intron_variant	Intron 1 of 7	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16612 AN: 152086 Hom.: 1879 Cov.: 34

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0679

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0893

GnomAD2 exomes AF: 0.0600 AC: 11223 AN: 187028 AF XY: 0.0569

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0643

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0437 AC: 62082 AN: 1419578 Hom.: 2692 Cov.: 30 AF XY: 0.0435 AC XY: 30584 AN XY: 703624

African (AFR) AF: 0.305 AC: 10155 AN: 33276

American (AMR) AF: 0.0388 AC: 1499 AN: 38680

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 1561 AN: 25490

East Asian (EAS) AF: 0.0151 AC: 585 AN: 38826

South Asian (SAS) AF: 0.0588 AC: 4815 AN: 81922

European-Finnish (FIN) AF: 0.0633 AC: 2390 AN: 37784

Middle Eastern (MID) AF: 0.0932 AC: 534 AN: 5728

European-Non Finnish (NFE) AF: 0.0338 AC: 37110 AN: 1098420

Other (OTH) AF: 0.0577 AC: 3433 AN: 59452

GnomAD4 genome AF: 0.109 AC: 16647 AN: 152204 Hom.: 1883 Cov.: 34 AF XY: 0.109 AC XY: 8087 AN XY: 74436

African (AFR) AF: 0.290 AC: 12008 AN: 41462

American (AMR) AF: 0.0529 AC: 810 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3468

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5184

South Asian (SAS) AF: 0.0511 AC: 247 AN: 4830

European-Finnish (FIN) AF: 0.0679 AC: 721 AN: 10614

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2357 AN: 68020

Other (OTH) AF: 0.0898 AC: 190 AN: 2116

Alfa AF: 0.0693 Hom.: 280

Bravo AF: 0.117

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-III-A Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.1
DANN	Benign	0.85
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9900509; hg19: chr17-78191036;