rs544927524

chr7-65960907-A-Gchr7-65960907-A-Tchr7-65960907-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000181.4(GUSB):c.1946T>C(p.Leu649Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,612,328 control chromosomes in the GnomAD database, including 260,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. L649L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.52 (21363 hom., cov: 30)
  • Exomes 𝑓: 0.57 (239008 hom.)
• Consequence: GUSB NM_000181.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.232

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0806422E-6).
• BP6: Variant 7-65960907-A-G is Benign according to our data. Variant chr7-65960907-A-G is described in ClinVar as [Benign]. Clinvar id is 92588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65960907-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.1946T>C	p.Leu649Pro	missense_variant	12/12	ENST00000304895.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUSB	ENST00000304895.9	c.1946T>C	p.Leu649Pro	missense_variant	12/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78643 AN: 151644 Hom.: 21348 Cov.: 30

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.528

GnomAD3 exomes AF: 0.585 AC: 147110 AN: 251348 Hom.: 44250 AF XY: 0.590 AC XY: 80200 AN XY: 135838

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.836

Gnomad SAS exome AF: 0.643

Gnomad FIN exome AF: 0.624

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.567 AC: 828239 AN: 1460566 Hom.: 239008 Cov.: 38 AF XY: 0.571 AC XY: 414733 AN XY: 726652

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.550

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.880

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.621

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.519 AC: 78690 AN: 151762 Hom.: 21363 Cov.: 30 AF XY: 0.524 AC XY: 38859 AN XY: 74158

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.837

Gnomad4 SAS AF: 0.655

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.531

Alfa AF: 0.559 Hom.: 61957

Bravo AF: 0.507

TwinsUK AF: 0.553 AC: 2049

ALSPAC AF: 0.552 AC: 2126

ESP6500AA AF: 0.369 AC: 1628

ESP6500EA AF: 0.553 AC: 4756

ExAC AF: 0.580 AC: 70366

Asia WGS AF: 0.717 AC: 2495 AN: 3478

EpiCase AF: 0.560

EpiControl AF: 0.559

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 58% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2018	Variant summary: GUSB c.1946T>C (p.Leu649Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.58 in 276996 control chromosomes, suggesting that it is the major allele and therefore benign. To our knowledge, no occurrence of c.1946T>C in individuals affected with Mucopolysaccharidosis Type VI (Sly Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2013	- -

Mucopolysaccharidosis type 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	5.4
Dann	Benign	0.50
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.23	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.24
Sift	Benign	0.71	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.0	B;.
Vest4		0.029
MPC		0.64
ClinPred		0.0069	T
GERP RS		-0.066
Varity_R		0.045
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs9530; hg19: chr7-65425894; COSMIC: COSV59221316; COSMIC: COSV59221316;