rs6780220

Variant names:

• chr3-33045708-A-C
• rs6780220
• NM_000404.4:c.1068+412T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000404.4(GLB1):​c.1068+412T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,075,154 control chromosomes in the GnomAD database, including 17,601 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3295 hom., cov: 31)
  • Exomes 𝑓: 0.17 (14306 hom.)
• Consequence: GLB1 NM_000404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 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.1068+412T>G		intron	N/A	NP_000395.3
	GLB1	NM_001317040.2		c.1212+412T>G		intron	N/A	NP_001303969.2
	GLB1	NM_001079811.3		c.978+412T>G		intron	N/A	NP_001073279.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.1068+412T>G		intron	N/A	ENSP00000306920.4	P16278
	GLB1	ENST00000307377.12	TSL:1	c.675+412T>G		intron	N/A	ENSP00000305920.8	E7EQ29
	GLB1	ENST00000399402.7	TSL:2	c.978+412T>G		intron	N/A	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28840 AN: 151888 Hom.: 3281 Cov.: 31

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.164

GnomAD4 exome AF: 0.169 AC: 156050 AN: 923148 Hom.: 14306 Cov.: 32 AF XY: 0.170 AC XY: 73334 AN XY: 431498

African (AFR) AF: 0.204 AC: 4006 AN: 19596

American (AMR) AF: 0.149 AC: 1027 AN: 6870

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 1016 AN: 7366

East Asian (EAS) AF: 0.557 AC: 5246 AN: 9424

South Asian (SAS) AF: 0.271 AC: 7704 AN: 28378

European-Finnish (FIN) AF: 0.159 AC: 527 AN: 3310

Middle Eastern (MID) AF: 0.126 AC: 246 AN: 1946

European-Non Finnish (NFE) AF: 0.160 AC: 130044 AN: 814328

Other (OTH) AF: 0.195 AC: 6234 AN: 31930

GnomAD4 genome AF: 0.190 AC: 28890 AN: 152006 Hom.: 3295 Cov.: 31 AF XY: 0.195 AC XY: 14485 AN XY: 74286

African (AFR) AF: 0.203 AC: 8405 AN: 41446

American (AMR) AF: 0.147 AC: 2249 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3466

East Asian (EAS) AF: 0.556 AC: 2858 AN: 5140

South Asian (SAS) AF: 0.298 AC: 1436 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1932 AN: 10554

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11022 AN: 67982

Other (OTH) AF: 0.172 AC: 362 AN: 2110

Alfa AF: 0.170 Hom.: 5924

Bravo AF: 0.186

Asia WGS AF: 0.380 AC: 1322 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.7
DANN	Benign	0.21
PhyloP100		-2.1
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: rs6780220; hg19: chr3-33087200;