rs140016611

Variant names:

• chr7-65980398-G-A
• rs140016611
• NM_000181.4:c.222C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-65980398-G-A
• chr7-65980398-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001293104.2(GUSB):​c.-164C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,162 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: GUSB NM_001293104.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.143
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-65980398-G-A is Benign according to our data. Variant chr7-65980398-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 528234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00179 (272/152332) while in subpopulation NFE AF = 0.00285 (194/68030). AF 95% confidence interval is 0.00252. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293104.2. 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.222C>T	p.Thr74Thr	synonymous	Exon 2 of 12	NP_000172.2	P08236-1
	GUSB	NM_001293104.2		c.-164C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001280033.1
	GUSB	NM_001293105.2		c.-108C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001280034.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUSB	ENST00000304895.9	TSL:1 MANE Select	c.222C>T	p.Thr74Thr	synonymous	Exon 2 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000446111.1	TSL:1	n.222C>T		non_coding_transcript_exon	Exon 2 of 4	ENSP00000416793.1	F2Z3L6
	GUSB	ENST00000864783.1		c.222C>T	p.Thr74Thr	synonymous	Exon 2 of 12	ENSP00000534842.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00197 AC: 490 AN: 248160 AF XY: 0.00205

Gnomad AFR exome AF: 0.000946

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00284

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00229 AC: 3338 AN: 1460830 Hom.: 11 Cov.: 34 AF XY: 0.00224 AC XY: 1625 AN XY: 726612

African (AFR) AF: 0.000508 AC: 17 AN: 33458

American (AMR) AF: 0.00103 AC: 46 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86046

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53290

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00268 AC: 2984 AN: 1111564

Other (OTH) AF: 0.00184 AC: 111 AN: 60354

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74490

African (AFR) AF: 0.000890 AC: 37 AN: 41572

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00164

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00321

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.7
DANN	Uncertain	0.99
PhyloP100		0.14
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: rs140016611; hg19: chr7-65445385; COSMIC: COSV59221894; COSMIC: COSV59221894;