rs786205671

Positions:

• chr7-65979910-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The ENST00000304895.9(GUSB):​c.398G>C​(p.Trp133Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GUSB ENST00000304895.9 missense, splice_region
• Scores: Splicing: ADA: 0.9028
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.26

Genes affected

GUSB (HGNC:4696): (glucuronidase beta) This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-65979910-C-G is Pathogenic according to our data. Variant chr7-65979910-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190460.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUSB	NM_000181.4	c.398G>C	p.Trp133Ser	missense_variant, splice_region_variant	3/12	ENST00000304895.9	NP_000172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUSB	ENST00000304895.9	c.398G>C	p.Trp133Ser	missense_variant, splice_region_variant	3/12	1	NM_000181.4	ENSP00000302728	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-immune hydrops fetalis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 19, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.91		Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.12		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: rs786205671; hg19: chr7-65444897;