NM_000181.4:c.1061C>T

Variant names:

• chr7-65974923-G-A
• rs121918175
• NM_000181.4:c.1061C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_000181.4(GUSB):​c.1061C>T​(p.Ala354Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,326 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005377915: "Published functional studies demonstrate a damaging effect on residual enzymatic activity (PMID:8111413)."". Synonymous variant affecting the same amino acid position (i.e. A354A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GUSB NM_000181.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.53
• Publications: 7 publications found

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]

GUSB Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005377915: "Published functional studies demonstrate a damaging effect on residual enzymatic activity (PMID: 8111413)."
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000181.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-65974923-G-A is Pathogenic according to our data. Variant chr7-65974923-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 896.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000181.4. 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
	GUSB	NM_000181.4	MANE Select	c.1061C>T	p.Ala354Val	missense	Exon 6 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.623C>T	p.Ala208Val	missense	Exon 4 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.491C>T	p.Ala164Val	missense	Exon 5 of 11	NP_001280033.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUSB	ENST00000304895.9	TSL:1 MANE Select	c.1061C>T	p.Ala354Val	missense	Exon 6 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000864783.1		c.1145C>T	p.Ala382Val	missense	Exon 6 of 12	ENSP00000534842.1
	GUSB	ENST00000864792.1		c.1124C>T	p.Ala375Val	missense	Exon 6 of 12	ENSP00000534851.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251142 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461326 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726972

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000330 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Mucopolysaccharidosis type 7 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.86		Loss of ubiquitination at K350 (P = 0.0648)
MVP		0.97
MPC		1.1
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.81
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121918175; hg19: chr7-65439910;