rs34421970

Variant names:

• chr3-33018489-G-A
• rs34421970
• NM_000404.4:c.1306C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-33018489-G-A
• chr3-33018489-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000404.4(GLB1):​c.1306C>T​(p.Leu436Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,982 control chromosomes in the GnomAD database, including 159 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L436V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (6 hom., cov: 31)
  • Exomes 𝑓: 0.013 (153 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.568
• Publications: 16 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: ClinGen, Myriad Women’s Health
• GM1 gangliosidosis type 3

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

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 3 uncertain in NM_000404.4
• 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 3, GM1 gangliosidosis type 2, GM1 gangliosidosis type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032697916).
• BP6: Variant 3-33018489-G-A is Benign according to our data. Variant chr3-33018489-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92895.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 = 0.00939 (1429/152118) while in subpopulation NFE AF = 0.0142 (964/67998). AF 95% confidence interval is 0.0134. There are 6 homozygotes in GnomAd4. There are 683 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1306C>T	p.Leu436Phe	missense	Exon 13 of 16	NP_000395.3
	GLB1	NM_001317040.2		c.1450C>T	p.Leu484Phe	missense	Exon 14 of 17	NP_001303969.2
	GLB1	NM_001079811.3		c.1216C>T	p.Leu406Phe	missense	Exon 13 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.1306C>T	p.Leu436Phe	missense	Exon 13 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000307377.12	TSL:1	c.913C>T	p.Leu305Phe	missense	Exon 10 of 13	ENSP00000305920.8	E7EQ29
	GLB1	ENST00000399402.7	TSL:2	c.1216C>T	p.Leu406Phe	missense	Exon 13 of 16	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1433 AN: 152000 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00676

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00868

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0115 AC: 2868 AN: 249586 AF XY: 0.0115

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0132 AC: 19249 AN: 1461864 Hom.: 153 Cov.: 32 AF XY: 0.0129 AC XY: 9400 AN XY: 727232

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00505 AC: 226 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 1013 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00664 AC: 573 AN: 86258

European-Finnish (FIN) AF: 0.0122 AC: 651 AN: 53412

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.0143 AC: 15931 AN: 1111994

Other (OTH) AF: 0.0121 AC: 733 AN: 60392

GnomAD4 genome AF: 0.00939 AC: 1429 AN: 152118 Hom.: 6 Cov.: 31 AF XY: 0.00919 AC XY: 683 AN XY: 74360

African (AFR) AF: 0.00231 AC: 96 AN: 41480

American (AMR) AF: 0.00675 AC: 103 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.00868 AC: 92 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 964 AN: 67998

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0131 Hom.: 62

Bravo AF: 0.00915

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00303 AC: 12

ESP6500EA AF: 0.0140 AC: 117

ExAC AF: 0.0122 AC: 1472

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0126

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	GLB1-related disorder (1)
-	-	1	GM1 gangliosidosis (1)
-	-	1	GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)
-	-	1	Mucopolysaccharidosis, MPS-IV-B (1)
-	-	1	Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.0080
DANN	Benign	0.34
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.33	T
PhyloP100		-0.57
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.24
Sift	Benign	0.82	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.070
MPC		0.26
ClinPred		0.0062	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.75
Mutation Taster		=77/23	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: rs34421970; hg19: chr3-33059981;