3-33014196-T-C

Variant names:

• chr3-33014196-T-C
• rs73826339
• NM_000404.4:c.1594A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000404.4(GLB1):​c.1594A>G​(p.Ser532Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 1,614,094 control chromosomes in the GnomAD database, including 2,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.050 (233 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2470 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -2.81
• Publications: 22 publications found

Genes affected

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

GLB1 Gene-Disease associations (from GenCC):

• GM1 gangliosidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• GM1 gangliosidosis type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• GM1 gangliosidosis type 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 0.79419 (below the threshold of 3.09). Trascript score misZ: 1.1264 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 4B, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017570257).
• BP6: Variant 3-33014196-T-C is Benign according to our data. Variant chr3-33014196-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000404.4. 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
	GLB1	NM_000404.4	MANE Select	c.1594A>G	p.Ser532Gly	missense	Exon 15 of 16	NP_000395.3
	GLB1	NM_001317040.2		c.1738A>G	p.Ser580Gly	missense	Exon 16 of 17	NP_001303969.2
	GLB1	NM_001079811.3		c.1504A>G	p.Ser502Gly	missense	Exon 15 of 16	NP_001073279.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.1594A>G	p.Ser532Gly	missense	Exon 15 of 16	ENSP00000306920.4
	GLB1	ENST00000307377.12	TSL:1	c.1201A>G	p.Ser401Gly	missense	Exon 12 of 13	ENSP00000305920.8
	GLB1	ENST00000399402.7	TSL:2	c.1504A>G	p.Ser502Gly	missense	Exon 15 of 16	ENSP00000382333.2

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7630 AN: 152094 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0617

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0470 AC: 11658 AN: 248130 AF XY: 0.0464

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.0907

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0555 AC: 81160 AN: 1461882 Hom.: 2470 Cov.: 31 AF XY: 0.0544 AC XY: 39585 AN XY: 727238

African (AFR) AF: 0.0348 AC: 1166 AN: 33480

American (AMR) AF: 0.0426 AC: 1904 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 2417 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0110 AC: 949 AN: 86258

European-Finnish (FIN) AF: 0.0418 AC: 2234 AN: 53420

Middle Eastern (MID) AF: 0.0719 AC: 415 AN: 5768

European-Non Finnish (NFE) AF: 0.0617 AC: 68661 AN: 1112000

Other (OTH) AF: 0.0564 AC: 3409 AN: 60396

GnomAD4 genome AF: 0.0501 AC: 7629 AN: 152212 Hom.: 233 Cov.: 32 AF XY: 0.0478 AC XY: 3555 AN XY: 74422

African (AFR) AF: 0.0336 AC: 1394 AN: 41534

American (AMR) AF: 0.0647 AC: 989 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 265 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4808

European-Finnish (FIN) AF: 0.0405 AC: 430 AN: 10606

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0616 AC: 4192 AN: 68012

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0581 Hom.: 555

Bravo AF: 0.0526

TwinsUK AF: 0.0583 AC: 216

ALSPAC AF: 0.0599 AC: 231

ESP6500AA AF: 0.0331 AC: 133

ESP6500EA AF: 0.0607 AC: 504

ExAC AF: 0.0465 AC: 5619

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0698

EpiControl AF: 0.0741

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	2	Mucopolysaccharidosis, MPS-IV-B (2)
-	-	1	GLB1-related disorder (1)
-	-	1	GM1 gangliosidosis (1)
-	-	1	GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)
-	-	1	Infantile GM1 gangliosidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.046
DANN	Benign	0.77
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.51	T
PhyloP100		-2.8
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.20
Sift	Benign	0.38	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.044
MPC		0.22
ClinPred		0.00052	T
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs73826339; hg19: chr3-33055688;