3-33097057-G-A

Variant names:

• chr3-33097057-G-A
• rs7637099
• NM_000404.4:c.29C>T

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.29C>T​(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,612,026 control chromosomes in the GnomAD database, including 286,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20875 hom., cov: 36)
  • Exomes 𝑓: 0.60 (265447 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 0.206
• Publications: 42 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]

TMPPE (HGNC:33865): (transmembrane protein with metallophosphoesterase domain) Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=1.3571978E-4).
• BP6: Variant 3-33097057-G-A is Benign according to our data. Variant chr3-33097057-G-A is described in ClinVar as Benign. ClinVar VariationId is 92904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 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.29C>T	p.Pro10Leu	missense	Exon 1 of 16	NP_000395.3
	TMPPE	NM_001039770.3	MANE Select	c.-447C>T		5_prime_UTR	Exon 1 of 2	NP_001034859.2	Q6ZT21-1
	GLB1	NM_001317040.2		c.29C>T	p.Pro10Leu	missense	Exon 1 of 17	NP_001303969.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.29C>T	p.Pro10Leu	missense	Exon 1 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000307377.12	TSL:1	c.29C>T	p.Pro10Leu	missense	Exon 1 of 13	ENSP00000305920.8	E7EQ29
	TMPPE	ENST00000342462.5	TSL:2 MANE Select	c.-447C>T		5_prime_UTR	Exon 1 of 2	ENSP00000343398.4	Q6ZT21-1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73156 AN: 152100 Hom.: 20873 Cov.: 36

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.567 AC: 139166 AN: 245256 AF XY: 0.578

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.513

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.598 AC: 872782 AN: 1459818 Hom.: 265447 Cov.: 85 AF XY: 0.599 AC XY: 435262 AN XY: 726242

African (AFR) AF: 0.135 AC: 4518 AN: 33352

American (AMR) AF: 0.546 AC: 24308 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 17698 AN: 26032

East Asian (EAS) AF: 0.512 AC: 20249 AN: 39570

South Asian (SAS) AF: 0.572 AC: 49229 AN: 86024

European-Finnish (FIN) AF: 0.601 AC: 32052 AN: 53358

Middle Eastern (MID) AF: 0.635 AC: 3656 AN: 5758

European-Non Finnish (NFE) AF: 0.618 AC: 685979 AN: 1110894

Other (OTH) AF: 0.582 AC: 35093 AN: 60300

GnomAD4 genome AF: 0.481 AC: 73158 AN: 152208 Hom.: 20875 Cov.: 36 AF XY: 0.483 AC XY: 35950 AN XY: 74424

African (AFR) AF: 0.150 AC: 6247 AN: 41562

American (AMR) AF: 0.575 AC: 8786 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2330 AN: 3470

East Asian (EAS) AF: 0.514 AC: 2654 AN: 5166

South Asian (SAS) AF: 0.548 AC: 2649 AN: 4832

European-Finnish (FIN) AF: 0.592 AC: 6277 AN: 10610

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.622 AC: 42287 AN: 67958

Other (OTH) AF: 0.530 AC: 1121 AN: 2114

Alfa AF: 0.572 Hom.: 93596

Bravo AF: 0.462

TwinsUK AF: 0.618 AC: 2290

ALSPAC AF: 0.625 AC: 2410

ESP6500AA AF: 0.160 AC: 641

ESP6500EA AF: 0.624 AC: 5237

ExAC AF: 0.560 AC: 67538

Asia WGS AF: 0.511 AC: 1769 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	3	Mucopolysaccharidosis, MPS-IV-B (3)
-	-	2	Infantile GM1 gangliosidosis (2)
-	-	1	GM1 gangliosidosis (2)
-	-	1	GM1 gangliosidosis type 2 (1)
-	-	1	GM1 gangliosidosis type 3 (1)
-	-	1	GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.7
DANN	Benign	0.87
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.79	T
PhyloP100		0.21
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.36
Sift	Benign	0.68	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.76
ClinPred		0.0029	T
GERP RS		-0.13
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
gMVP		0.57
Mutation Taster		=98/2	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: rs7637099; hg19: chr3-33138549; COSMIC: COSV56561124; COSMIC: COSV56561124;