rs1943534534

Variant names:

• chr11-134345068-T-C
• rs1943534534
• NM_001370461.1:c.388T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001370461.1(GLB1L2):​c.388T>C​(p.Trp130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLB1L2 NM_001370461.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82
• Publications: 0 publications found

Genes affected

GLB1L2 (HGNC:25129): (galactosidase beta 1 like 2) Predicted to enable beta-galactosidase activity. Predicted to be involved in carbohydrate metabolic process. Predicted to be located in extracellular region. Predicted to be active in vacuole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370461.1. 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
	GLB1L2	NM_001370461.1	MANE Select	c.388T>C	p.Trp130Arg	missense	Exon 4 of 19	NP_001357390.1	Q8IW92
	GLB1L2	NM_001370460.1		c.388T>C	p.Trp130Arg	missense	Exon 4 of 20	NP_001357389.1
	GLB1L2	NM_138342.4		c.388T>C	p.Trp130Arg	missense	Exon 4 of 20	NP_612351.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1L2	ENST00000535456.7	TSL:1 MANE Select	c.388T>C	p.Trp130Arg	missense	Exon 4 of 19	ENSP00000444628.1	Q8IW92
	GLB1L2	ENST00000855671.1		c.388T>C	p.Trp130Arg	missense	Exon 4 of 18	ENSP00000525730.1
	GLB1L2	ENST00000855672.1		c.87-2257T>C		intron	N/A	ENSP00000525731.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726786

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111640

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.023	D
Polyphen		0.97	D
Vest4		0.79
MutPred		0.82		Gain of methylation at W130 (P = 0.0335)
MVP		0.70
MPC		0.59
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.85
gMVP		0.97
Mutation Taster		=41/59	disease causing

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: rs1943534534; hg19: chr11-134214962;