NM_000181.4:c.1790-4G>T

Variant names:

• chr7-65961067-C-A
• rs879010457
• NM_000181.4:c.1790-4G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000181.4(GUSB):​c.1790-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GUSB NM_000181.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002440
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.296
• 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: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-65961067-C-A is Benign according to our data. Variant chr7-65961067-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 458509.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUSB	NM_000181.4	c.1790-4G>T		splice_region_variant, intron_variant	Intron 11 of 11	ENST00000304895.9	NP_000172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUSB	ENST00000304895.9	c.1790-4G>T		splice_region_variant, intron_variant	Intron 11 of 11	1	NM_000181.4	ENSP00000302728.4

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 217 AN: 106558 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.000263

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.00205

GnomAD2 exomes AF: 0.0301 AC: 4803 AN: 159490 AF XY: 0.0295

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.0255

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0314

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00748 AC: 10087 AN: 1348104 Hom.: 0 Cov.: 35 AF XY: 0.00794 AC XY: 5355 AN XY: 674436

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0183 AC: 573 AN: 31272

American (AMR) AF: 0.0451 AC: 1953 AN: 43328

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 322 AN: 25174

East Asian (EAS) AF: 0.00615 AC: 237 AN: 38560

South Asian (SAS) AF: 0.0195 AC: 1622 AN: 83366

European-Finnish (FIN) AF: 0.0401 AC: 1875 AN: 46738

Middle Eastern (MID) AF: 0.0155 AC: 77 AN: 4964

European-Non Finnish (NFE) AF: 0.00300 AC: 3059 AN: 1018242

Other (OTH) AF: 0.00654 AC: 369 AN: 56460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00205 AC: 218 AN: 106592 Hom.: 0 Cov.: 29 AF XY: 0.00222 AC XY: 113 AN XY: 50814

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00120 AC: 34 AN: 28244

American (AMR) AF: 0.000591 AC: 6 AN: 10150

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2654

East Asian (EAS) AF: 0.000264 AC: 1 AN: 3788

South Asian (SAS) AF: 0.00172 AC: 6 AN: 3492

European-Finnish (FIN) AF: 0.0119 AC: 71 AN: 5970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00192 AC: 96 AN: 50048

Other (OTH) AF: 0.00204 AC: 3 AN: 1472

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00451 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 7 Benign:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.17
DANN	Benign	0.70
PhyloP100		-0.30
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.016
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: rs879010457; hg19: chr7-65426054;