NM_000199.5:c.166C>A

Variant names:

• chr17-80217115-G-T
• rs761780038
• NM_000199.5:c.166C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000199.5(SGSH):​c.166C>A​(p.Arg56Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,762 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01
• Publications: 0 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]

SGSH Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000199.5
• 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.166C>A	p.Arg56Ser	missense	Exon 2 of 8	NP_000190.1
	SGSH	NM_001352921.3		c.166C>A	p.Arg56Ser	missense	Exon 2 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.166C>A	p.Arg56Ser	missense	Exon 2 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.166C>A	p.Arg56Ser	missense	Exon 2 of 8	ENSP00000314606.6
	SGSH	ENST00000575282.5	TSL:1	n.175C>A		non_coding_transcript_exon	Exon 2 of 5
	SGSH	ENST00000874335.1		c.166C>A	p.Arg56Ser	missense	Exon 2 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448762 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719892

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

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 42404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.00 AC: 0 AN: 84382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107562

Other (OTH) AF: 0.0000167 AC: 1 AN: 59918

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.81	L
PhyloP100		6.0
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.52
Sift	Benign	0.26	T
Sift4G	Benign	0.27	T
Polyphen		0.093	B
Vest4		0.70
MutPred		0.49		Gain of sheet (P = 0.0149)
MVP		0.98
MPC		0.29
ClinPred		0.87	D
GERP RS		3.3
Varity_R		0.66
gMVP		0.88

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: rs761780038; hg19: chr17-78190914;