17-80217231-C-T

Variant names:

• chr17-80217231-C-T
• rs9900502
• NM_000199.5:c.89-39G>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.89-39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,577,028 control chromosomes in the GnomAD database, including 4,337 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 (1758 hom., cov: 33)
  • Exomes 𝑓: 0.044 (2579 hom.)
• Consequence: SGSH NM_000199.5 intron
• Scores: Splicing: ADA: 0.0002776
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.196
• Publications: 6 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, ClinGen, Myriad Women’s Health, PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-80217231-C-T is Benign according to our data. Variant chr17-80217231-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	NM_000199.5	MANE Select	c.89-39G>A		intron	N/A	NP_000190.1	P51688
	SGSH	NM_001352921.3		c.89-39G>A		intron	N/A	NP_001339850.1
	SGSH	NM_001352922.2		c.89-39G>A		intron	N/A	NP_001339851.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.89-39G>A		intron	N/A	ENSP00000314606.6	P51688
	SGSH	ENST00000575282.5	TSL:1	n.98-39G>A		intron	N/A
	SGSH	ENST00000874335.1		c.89-39G>A		intron	N/A	ENSP00000544394.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16250 AN: 152132 Hom.: 1755 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0888

GnomAD2 exomes AF: 0.0593 AC: 11534 AN: 194566 AF XY: 0.0563

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.0185

Gnomad FIN exome AF: 0.0634

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0437 AC: 62226 AN: 1424778 Hom.: 2579 Cov.: 31 AF XY: 0.0435 AC XY: 30714 AN XY: 706492

African (AFR) AF: 0.294 AC: 9813 AN: 33342

American (AMR) AF: 0.0381 AC: 1502 AN: 39404

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 1564 AN: 25574

East Asian (EAS) AF: 0.0224 AC: 872 AN: 38924

South Asian (SAS) AF: 0.0587 AC: 4833 AN: 82360

European-Finnish (FIN) AF: 0.0631 AC: 2441 AN: 38656

Middle Eastern (MID) AF: 0.0924 AC: 530 AN: 5736

European-Non Finnish (NFE) AF: 0.0338 AC: 37226 AN: 1101158

Other (OTH) AF: 0.0578 AC: 3445 AN: 59624

GnomAD4 genome AF: 0.107 AC: 16283 AN: 152250 Hom.: 1758 Cov.: 33 AF XY: 0.106 AC XY: 7915 AN XY: 74464

African (AFR) AF: 0.280 AC: 11610 AN: 41466

American (AMR) AF: 0.0521 AC: 797 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 206 AN: 3470

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5182

South Asian (SAS) AF: 0.0509 AC: 246 AN: 4834

European-Finnish (FIN) AF: 0.0678 AC: 721 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0347 AC: 2359 AN: 68040

Other (OTH) AF: 0.0893 AC: 189 AN: 2116

Alfa AF: 0.0700 Hom.: 1355

Bravo AF: 0.114

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mucopolysaccharidosis, MPS-III-A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.030		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: rs9900502; hg19: chr17-78191030;