rs4302331

Variant names:

• chr3-33014229-A-G
• rs4302331
• NM_000404.4:c.1561T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-33014229-A-G
• chr3-33014229-A-T
• chr3-33014229-A-C

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.1561T>C​(p.Cys521Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,614,086 control chromosomes in the GnomAD database, including 788,793 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C521S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.94 (67438 hom., cov: 30)
  • Exomes 𝑓: 0.99 (721355 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.385
• Publications: 41 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 -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 3, GM1 gangliosidosis type 2, GM1 gangliosidosis type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=7.181308E-7).
• BP6: Variant 3-33014229-A-G is Benign according to our data. Variant chr3-33014229-A-G is described in ClinVar as Benign. ClinVar VariationId is 167145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 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.1561T>C	p.Cys521Arg	missense	Exon 15 of 16	NP_000395.3
	GLB1	NM_001317040.2		c.1705T>C	p.Cys569Arg	missense	Exon 16 of 17	NP_001303969.2
	GLB1	NM_001079811.3		c.1471T>C	p.Cys491Arg	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.1561T>C	p.Cys521Arg	missense	Exon 15 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000307377.12	TSL:1	c.1168T>C	p.Cys390Arg	missense	Exon 12 of 13	ENSP00000305920.8	E7EQ29
	GLB1	ENST00000399402.7	TSL:2	c.1471T>C	p.Cys491Arg	missense	Exon 15 of 16	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142425 AN: 152080 Hom.: 67394 Cov.: 30

Gnomad AFR AF: 0.781

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.954

GnomAD2 exomes AF: 0.983 AC: 243454 AN: 247642 AF XY: 0.987

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.987

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.993 AC: 1451358 AN: 1461888 Hom.: 721355 Cov.: 92 AF XY: 0.994 AC XY: 722658 AN XY: 727244

African (AFR) AF: 0.773 AC: 25883 AN: 33480

American (AMR) AF: 0.985 AC: 44031 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26111 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 0.999 AC: 86203 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53420 AN: 53420

Middle Eastern (MID) AF: 0.988 AC: 5694 AN: 5766

European-Non Finnish (NFE) AF: 0.999 AC: 1110861 AN: 1112010

Other (OTH) AF: 0.984 AC: 59455 AN: 60396

GnomAD4 genome AF: 0.936 AC: 142526 AN: 152198 Hom.: 67438 Cov.: 30 AF XY: 0.938 AC XY: 69839 AN XY: 74424

African (AFR) AF: 0.781 AC: 32407 AN: 41470

American (AMR) AF: 0.974 AC: 14900 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3467 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 0.999 AC: 4815 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67928 AN: 68020

Other (OTH) AF: 0.954 AC: 2017 AN: 2114

Alfa AF: 0.975 Hom.: 166119

Bravo AF: 0.927

TwinsUK AF: 0.998 AC: 3701

ALSPAC AF: 0.998 AC: 3848

ESP6500AA AF: 0.798 AC: 3216

ESP6500EA AF: 0.998 AC: 8289

ExAC AF: 0.980 AC: 118416

Asia WGS AF: 0.988 AC: 3436 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Infantile GM1 gangliosidosis (2)
-	-	2	Mucopolysaccharidosis, MPS-IV-B (2)
-	-	2	not provided (3)
-	-	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	0.041
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.4
DANN	Benign	0.47
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.39
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.13
Sift	Benign	0.75	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.41
ClinPred		0.00053	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.70
Mutation Taster		=99/1	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: rs4302331; hg19: chr3-33055721; COSMIC: COSV107321333; COSMIC: COSV107321333;