NM_000199.5:c.175C>T

Variant names:

• chr17-80217106-G-A
• rs1555622928
• NM_000199.5:c.175C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000199.5(SGSH):​c.175C>T​(p.Leu59Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000199.5
• 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	c.175C>T	p.Leu59Phe	missense_variant	Exon 2 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.175C>T	p.Leu59Phe	missense_variant	Exon 2 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453486 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Uncertain:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	4.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.56
Sift	Benign	0.050	D;.
Sift4G	Benign	0.072	T;.
Polyphen		0.62	P;.
Vest4		0.34
MutPred		0.56		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.93
MPC		0.45
ClinPred		0.44	T
GERP RS		-7.3
Varity_R		0.48
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1555622928; hg19: chr17-78190905;