NM_000404.4:c.1233+8T>C

Variant names:

• chr3-33021558-A-G
• rs13093698
• NM_000404.4:c.1233+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000404.4(GLB1):​c.1233+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,234 control chromosomes in the GnomAD database, including 37,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3418 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33993 hom.)
• Consequence: GLB1 NM_000404.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002256
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 2.80
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-33021558-A-G is Benign according to our data. Variant chr3-33021558-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 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.1233+8T>C		splice_region intron	N/A	NP_000395.3
	GLB1	NM_001317040.2		c.1377+8T>C		splice_region intron	N/A	NP_001303969.2
	GLB1	NM_001079811.3		c.1143+8T>C		splice_region 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.1233+8T>C		splice_region intron	N/A	ENSP00000306920.4
	GLB1	ENST00000307377.12	TSL:1	c.840+8T>C		splice_region intron	N/A	ENSP00000305920.8
	GLB1	ENST00000399402.7	TSL:2	c.1143+8T>C		splice_region intron	N/A	ENSP00000382333.2

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31572 AN: 152040 Hom.: 3417 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.194 AC: 48010 AN: 246848 AF XY: 0.193

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.0569

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.213 AC: 310751 AN: 1460076 Hom.: 33993 Cov.: 33 AF XY: 0.211 AC XY: 153326 AN XY: 726178

African (AFR) AF: 0.222 AC: 7433 AN: 33466

American (AMR) AF: 0.191 AC: 8510 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5957 AN: 26056

East Asian (EAS) AF: 0.0598 AC: 2374 AN: 39686

South Asian (SAS) AF: 0.157 AC: 13462 AN: 85956

European-Finnish (FIN) AF: 0.202 AC: 10796 AN: 53328

Middle Eastern (MID) AF: 0.153 AC: 879 AN: 5760

European-Non Finnish (NFE) AF: 0.224 AC: 248708 AN: 1111000

Other (OTH) AF: 0.209 AC: 12632 AN: 60328

GnomAD4 genome AF: 0.208 AC: 31608 AN: 152158 Hom.: 3418 Cov.: 32 AF XY: 0.204 AC XY: 15167 AN XY: 74378

African (AFR) AF: 0.222 AC: 9227 AN: 41504

American (AMR) AF: 0.178 AC: 2715 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.0518 AC: 268 AN: 5178

South Asian (SAS) AF: 0.163 AC: 785 AN: 4822

European-Finnish (FIN) AF: 0.197 AC: 2089 AN: 10578

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15138 AN: 68004

Other (OTH) AF: 0.199 AC: 421 AN: 2112

Alfa AF: 0.218 Hom.: 2461

Bravo AF: 0.207

Asia WGS AF: 0.139 AC: 482 AN: 3478

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	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
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.030
Splicevardb		2.0
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: rs13093698; hg19: chr3-33063050;