rs746037899

Variant names:

• chr17-80210831-C-A
• rs746037899
• NM_000199.5:c.1130G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80210831-C-A
• chr17-80210831-C-G
• chr17-80210831-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000199.5(SGSH):​c.1130G>T​(p.Arg377Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377H) has been classified as Likely pathogenic.

• 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: 6.03
• Publications: 5 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]

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000199.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80210831-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1297691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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.1130G>T	p.Arg377Leu	missense	Exon 8 of 8	NP_000190.1
	SGSH	NM_001352921.3		c.*217G>T		3_prime_UTR	Exon 8 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.*180G>T		3_prime_UTR	Exon 9 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.1130G>T	p.Arg377Leu	missense	Exon 8 of 8	ENSP00000314606.6
	SGSH	ENST00000575282.5	TSL:1	n.4013G>T		non_coding_transcript_exon	Exon 5 of 5
	SGSH	ENST00000874335.1		c.1166G>T	p.Arg389Leu	missense	Exon 9 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Mucopolysaccharidosis, MPS-III-A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.93		Loss of MoRF binding (P = 0.0268)
MVP		0.94
MPC		0.86
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746037899; hg19: chr17-78184630;