17-80220312-A-T

Variant names:

• chr17-80220312-A-T
• rs1488660868
• NM_000199.5:c.2T>A

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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913
• Publications: 2 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.2T>A	p.Met1?	start_lost	Exon 1 of 8	NP_000190.1	P51688
	SGSH	NM_001352921.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000314606.6	P51688
	SGSH	ENST00000575282.5	TSL:1	n.11T>A		non_coding_transcript_exon	Exon 1 of 5
	SLC26A11	ENST00000945513.1		c.-327A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000615572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1337786 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 658856

African (AFR) AF: 0.00 AC: 0 AN: 27160

American (AMR) AF: 0.00 AC: 0 AN: 30990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23694

East Asian (EAS) AF: 0.0000326 AC: 1 AN: 30698

South Asian (SAS) AF: 0.00 AC: 0 AN: 74770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3924

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1057772

Other (OTH) AF: 0.00 AC: 0 AN: 55708

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.61	D
PhyloP100		0.91
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		0.043	B
Vest4		0.76
MutPred		0.85		Gain of ubiquitination at M1 (P = 0.023)
MVP		0.97
ClinPred		0.98	D
GERP RS		2.0
PromoterAI		-0.58	Under-expression
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

Other links and lift over

dbSNP: rs1488660868; hg19: chr17-78194111;