7-65975066-C-G

Variant names:

• chr7-65975066-C-G
• NM_000181.4:c.918G>C
• GUSB p.Gln306His

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000181.4(GUSB):​c.918G>C​(p.Gln306His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUSB NM_000181.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.918G>C	p.Gln306His	missense	Exon 6 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.480G>C	p.Gln160His	missense	Exon 4 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.348G>C	p.Gln116His	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.918G>C	p.Gln306His	missense	Exon 6 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000864783.1		c.1002G>C	p.Gln334His	missense	Exon 6 of 12	ENSP00000534842.1
	GUSB	ENST00000864792.1		c.981G>C	p.Gln327His	missense	Exon 6 of 12	ENSP00000534851.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	1.3
DANN	Benign	0.66
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.65
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.24
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.61
Mutation Taster		=74/26	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-65440053;