3-32996691-A-G

Variant names:

• chr3-32996691-A-G
• rs12167
• NM_000404.4:c.*354T>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.*354T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 330,724 control chromosomes in the GnomAD database, including 10,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4406 hom., cov: 33)
  • Exomes 𝑓: 0.26 (6335 hom.)
• Consequence: GLB1 NM_000404.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-32996691-A-G is Benign according to our data. Variant chr3-32996691-A-G is described in ClinVar as Benign. ClinVar VariationId is 344778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.284 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.*354T>C		3_prime_UTR	Exon 16 of 16	NP_000395.3
	GLB1	NM_001317040.2		c.*354T>C		3_prime_UTR	Exon 17 of 17	NP_001303969.2
	GLB1	NM_001079811.3		c.*354T>C		3_prime_UTR	Exon 16 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.*354T>C		3_prime_UTR	Exon 16 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000399402.7	TSL:2	c.*354T>C		3_prime_UTR	Exon 16 of 16	ENSP00000382333.2	P16278
	GLB1	ENST00000307377.12	TSL:1	c.*354T>C		downstream_gene	N/A	ENSP00000305920.8	E7EQ29

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33623 AN: 152106 Hom.: 4398 Cov.: 33

Gnomad AFR AF: 0.0824

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.259 AC: 46230 AN: 178500 Hom.: 6335 Cov.: 2 AF XY: 0.257 AC XY: 24659 AN XY: 95814

African (AFR) AF: 0.0791 AC: 428 AN: 5410

American (AMR) AF: 0.302 AC: 2282 AN: 7554

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 1013 AN: 4506

East Asian (EAS) AF: 0.176 AC: 1371 AN: 7798

South Asian (SAS) AF: 0.242 AC: 7826 AN: 32286

European-Finnish (FIN) AF: 0.287 AC: 2367 AN: 8248

Middle Eastern (MID) AF: 0.164 AC: 107 AN: 652

European-Non Finnish (NFE) AF: 0.276 AC: 28509 AN: 103116

Other (OTH) AF: 0.261 AC: 2327 AN: 8930

GnomAD4 genome AF: 0.221 AC: 33642 AN: 152224 Hom.: 4406 Cov.: 33 AF XY: 0.223 AC XY: 16580 AN XY: 74426

African (AFR) AF: 0.0823 AC: 3421 AN: 41558

American (AMR) AF: 0.291 AC: 4446 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3472

East Asian (EAS) AF: 0.187 AC: 967 AN: 5176

South Asian (SAS) AF: 0.247 AC: 1193 AN: 4828

European-Finnish (FIN) AF: 0.309 AC: 3272 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19050 AN: 67988

Other (OTH) AF: 0.220 AC: 464 AN: 2112

Alfa AF: 0.259 Hom.: 11827

Bravo AF: 0.212

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	GM1 gangliosidosis (1)
-	-	1	Mucopolysaccharidosis, MPS-IV-B (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.84
DANN	Benign	0.81
PhyloP100		-1.1
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: rs12167; hg19: chr3-33038183;