Genetic Variant NM_000181.4:c.396+74A>T (chr7-65980150-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.447

Publications

1 publications found

Variant links:

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

GUSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUSB	NM_000181.4 link	c.396+74A>T		intron_variant	Intron 2 of 11	ENST00000304895.9	NP_000172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUSB	ENST00000304895.9 link	c.396+74A>T		intron_variant	Intron 2 of 11	1	NM_000181.4	ENSP00000302728.4

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

501

AN:

152118

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00500

AC XY:

3079

AN XY:

615618

show subpopulations

African (AFR)

AF:

0.000739

AC:

AN:

28424

American (AMR)

AF:

0.00191

AC:

AN:

35610

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

24168

East Asian (EAS)

AF:

0.00

AC:

AN:

35030

South Asian (SAS)

AF:

0.00110

AC:

AN:

75628

European-Finnish (FIN)

AF:

0.00411

AC:

193

AN:

46918

Middle Eastern (MID)

AF:

0.000802

AC:

AN:

3742

European-Non Finnish (NFE)

AF:

0.00626

AC:

5828

AN:

931588

Other (OTH)

AF:

0.00383

AC:

201

AN:

52420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

339

677

1016

1354

1693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00329

AC:

501

AN:

152236

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

223

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41542

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00396

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00544

AC:

370

AN:

67998

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.00304

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.1

(source)

DANN

Benign

0.78

PhyloP100

-0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over