chr17-80220312-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePP5_Moderate

The NM_000199.5(SGSH):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SGSH
NM_000199.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.913

Publications

2 publications found

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:

SLC26A11 (HGNC:14471): (solute carrier family 26 member 11) This gene encodes a member of the solute linked carrier 26 family of anion exchangers. Members of this family of proteins are essential for numerous cellular functions including homeostasis and intracellular electrolyte balance. The encoded protein is a sodium independent sulfate transporter that is sensitive to the anion exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

SLC26A11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 88 codons. Genomic position: 80215126. Lost 0.174 part of the original CDS.

PS1

Another start lost variant in NM_000199.5 (SGSH) was described as [Pathogenic] in ClinVar

PP5

Variant 17-80220312-A-C is Pathogenic according to our data. Variant chr17-80220312-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1460119.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 8	ENST00000326317.11	NP_000190.1	P51688
SLC26A11	NM_001166347.2 link	c.-398A>C		upstream_gene_variant		ENST00000361193.8	NP_001159819.1	Q86WA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 8	1	NM_000199.5	ENSP00000314606.6		P51688
SLC26A11	ENST00000361193.8 link	c.-398A>C		upstream_gene_variant		1	NM_001166347.2	ENSP00000355384.3		Q86WA9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000360

AC:

481

AN:

1336926

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

219

AN XY:

658450

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000221

AC:

AN:

27152

American (AMR)

AF:

0.0000323

AC:

AN:

30988

Ashkenazi Jewish (ASJ)

AF:

0.000169

AC:

AN:

23688

East Asian (EAS)

AF:

0.0000652

AC:

AN:

30698

South Asian (SAS)

AF:

0.0000936

AC:

AN:

74764

European-Finnish (FIN)

AF:

0.0000302

AC:

AN:

33068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3922

European-Non Finnish (NFE)

AF:

0.000425

AC:

449

AN:

1056964

Other (OTH)

AF:

0.000198

AC:

AN:

55682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.241

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74408

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:1

Oct 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts a region of the SGSH protein in which other variant(s) (p.Thr79Pro) have been determined to be pathogenic (PMID: 9285796, 11182930; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1460119). A different variant (c.1A>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 21204211, 21910976, 22976768). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SGSH mRNA. The next in-frame methionine is located at codon 88. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.87

PhyloP100

0.91

PROVEAN

Benign

-1.3

N;.;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.010

D;D;.

Polyphen

0.18

B;.;.

Vest4

0.69

MutPred

0.90

Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);

MVP

0.97

ClinPred

0.98

GERP RS

2.0

PromoterAI

-0.60

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.86

Mutation Taster

=12/188

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over