Genetic Variant SGSH:p.Met1? (chr17-80220312-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000199.5(SGSH):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SGSH
NM_000199.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

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:

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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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1337786

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

658856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27160

American (AMR)

AF:

0.00

AC:

AN:

30990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23694

East Asian (EAS)

AF:

0.0000326

AC:

AN:

30698

South Asian (SAS)

AF:

0.00

AC:

AN:

74770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

9.45e-7

AC:

AN:

1057772

Other (OTH)

AF:

0.00

AC:

AN:

55708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.61

PhyloP100

0.91

PROVEAN

Benign

-1.3

N;.;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.010

D;D;.

Polyphen

0.043

B;.;.

Vest4

0.76

MutPred

0.85

Gain of ubiquitination at M1 (P = 0.023);Gain of ubiquitination at M1 (P = 0.023);Gain of ubiquitination at M1 (P = 0.023);

MVP

0.97

ClinPred

0.98

GERP RS

2.0

PromoterAI

-0.58

Under-expression

(source)

Varity_R

0.94

gMVP

0.85

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

Computational scores

Splicing

Publications

Other links and lift over