rs781146

Variant names:

• chr7-65980150-T-A
• rs781146
• NM_000181.4:c.396+74A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000181.4(GUSB):​c.396+74A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,385,764 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (25 hom.)
• Consequence: GUSB NM_000181.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00329 (501/152236) while in subpopulation NFE AF = 0.00544 (370/67998). AF 95% confidence interval is 0.00498. There are 0 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

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.396+74A>T		intron	N/A	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.396+74A>T		intron	N/A	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.11+74A>T		intron	N/A	NP_001280033.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUSB	ENST00000304895.9	TSL:1 MANE Select	c.396+74A>T		intron	N/A	ENSP00000302728.4	P08236-1
	GUSB	ENST00000446111.1	TSL:1	n.396+74A>T		intron	N/A	ENSP00000416793.1	F2Z3L6
	GUSB	ENST00000864783.1		c.470A>T	p.His157Leu	missense	Exon 2 of 12	ENSP00000534842.1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00524 AC: 6467 AN: 1233528 Hom.: 25 AF XY: 0.00500 AC XY: 3079 AN XY: 615618

African (AFR) AF: 0.000739 AC: 21 AN: 28424

American (AMR) AF: 0.00191 AC: 68 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 70 AN: 24168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35030

South Asian (SAS) AF: 0.00110 AC: 83 AN: 75628

European-Finnish (FIN) AF: 0.00411 AC: 193 AN: 46918

Middle Eastern (MID) AF: 0.000802 AC: 3 AN: 3742

European-Non Finnish (NFE) AF: 0.00626 AC: 5828 AN: 931588

Other (OTH) AF: 0.00383 AC: 201 AN: 52420

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74426

African (AFR) AF: 0.00118 AC: 49 AN: 41542

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 67998

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00476 Hom.: 0

Bravo AF: 0.00304

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs781146; hg19: chr7-65445137;