17-80220313-T-A

Variant names:

• chr17-80220313-T-A
• rs1250300189
• NM_000199.5:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000199.5(SGSH):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,210 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: 7.5e-7 (0 hom.)
• Consequence: SGSH NM_000199.5 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 4 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]

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]

ACMG classification

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

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	NP_000190.1	P51688
	SGSH	NM_001352921.3		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 9	NP_001339851.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000314606.6	P51688
	SGSH	ENST00000575282.5	TSL:1	n.10A>T		non_coding_transcript_exon	Exon 1 of 5
	SGSH	ENST00000874335.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339210 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 659624

African (AFR) AF: 0.00 AC: 0 AN: 27188

American (AMR) AF: 0.00 AC: 0 AN: 31024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23688

East Asian (EAS) AF: 0.00 AC: 0 AN: 30682

South Asian (SAS) AF: 0.00 AC: 0 AN: 74816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059050

Other (OTH) AF: 0.00 AC: 0 AN: 55744

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	16
DANN	Benign	0.69
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.42	D
PhyloP100		-0.099
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.78	T
Polyphen		0.0040	B
Vest4		0.79
MutPred		0.91		Loss of catalytic residue at M1 (P = 0.1238)
MVP		0.88
ClinPred		0.84	D
GERP RS		2.0
PromoterAI		-0.53	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.93
gMVP		0.55

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

Other links and lift over

dbSNP: rs1250300189; hg19: chr17-78194112;