rs2279903

Variant names:

• chr7-65982195-C-T
• rs2279903
• NM_000181.4:c.-12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000181.4(GUSB):​c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,499,816 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (62 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (347 hom.)
• Consequence: GUSB NM_000181.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.73
• Publications: 6 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: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-65982195-C-T is Benign according to our data. Variant chr7-65982195-C-T is described in ClinVar as Benign. ClinVar VariationId is 360558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

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.-12G>A		5_prime_UTR	Exon 1 of 12	NP_000172.2
	GUSB	NM_001284290.2		c.-12G>A		5_prime_UTR	Exon 1 of 10	NP_001271219.1
	GUSB	NM_001293104.2		c.-397G>A		5_prime_UTR	Exon 1 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.-12G>A		5_prime_UTR	Exon 1 of 12	ENSP00000302728.4
	GUSB	ENST00000446111.1	TSL:1	n.-12G>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000416793.1
	GUSB	ENST00000446111.1	TSL:1	n.-12G>A		5_prime_UTR	Exon 1 of 4	ENSP00000416793.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2835 AN: 152248 Hom.: 59 Cov.: 31

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0897

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0213 AC: 2371 AN: 111254 AF XY: 0.0182

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.0876

Gnomad FIN exome AF: 0.0558

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.00922 AC: 12420 AN: 1347450 Hom.: 347 Cov.: 30 AF XY: 0.00903 AC XY: 5969 AN XY: 661160

African (AFR) AF: 0.0212 AC: 598 AN: 28230

American (AMR) AF: 0.0366 AC: 1209 AN: 33074

Ashkenazi Jewish (ASJ) AF: 0.00617 AC: 147 AN: 23826

East Asian (EAS) AF: 0.112 AC: 3682 AN: 32828

South Asian (SAS) AF: 0.00605 AC: 461 AN: 76164

European-Finnish (FIN) AF: 0.0542 AC: 1957 AN: 36138

Middle Eastern (MID) AF: 0.0104 AC: 48 AN: 4626

European-Non Finnish (NFE) AF: 0.00326 AC: 3440 AN: 1056540

Other (OTH) AF: 0.0157 AC: 878 AN: 56024

GnomAD4 genome AF: 0.0187 AC: 2855 AN: 152366 Hom.: 62 Cov.: 31 AF XY: 0.0213 AC XY: 1587 AN XY: 74510

African (AFR) AF: 0.0206 AC: 857 AN: 41594

American (AMR) AF: 0.0258 AC: 395 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0897 AC: 464 AN: 5170

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4834

European-Finnish (FIN) AF: 0.0622 AC: 661 AN: 10630

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68042

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0115 Hom.: 5

Bravo AF: 0.0166

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.96
DANN	Benign	0.71
PhyloP100		-1.7
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	polymorphism (auto)

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: rs2279903; hg19: chr7-65447182;