rs75548401

Variant names:

• chr1-155236246-G-A
• rs75548401
• NM_000157.4:c.1223C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000157.4(GBA1):​c.1223C>T​(p.Thr408Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,613,292 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T408T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (63 hom.)
• Consequence: GBA1 NM_000157.4 missense, splice_region
• Scores: Splicing: ADA: 0.007842
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13 O:1
• Conservation: PhyloP100: 1.87
• Publications: 129 publications found

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000157.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019058436).
• BP6: Variant 1-155236246-G-A is Benign according to our data. Variant chr1-155236246-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93447.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (915/152312) while in subpopulation NFE AF = 0.00929 (632/68018). AF 95% confidence interval is 0.00869. There are 5 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. 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
	GBA1	NM_000157.4	MANE Select	c.1223C>T	p.Thr408Met	missense splice_region	Exon 8 of 11	NP_000148.2
	GBA1	NM_001005741.3		c.1223C>T	p.Thr408Met	missense splice_region	Exon 9 of 12	NP_001005741.1
	GBA1	NM_001005742.3		c.1223C>T	p.Thr408Met	missense splice_region	Exon 9 of 12	NP_001005742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1223C>T	p.Thr408Met	missense splice_region	Exon 8 of 11	ENSP00000357357.3
	GBA1	ENST00000327247.9	TSL:1	c.1223C>T	p.Thr408Met	missense splice_region	Exon 9 of 12	ENSP00000314508.5
	GBA1	ENST00000948997.1		c.1289C>T	p.Thr430Met	missense splice_region	Exon 10 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 915 AN: 152194 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00594 AC: 1491 AN: 251106 AF XY: 0.00583

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00999

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00708 AC: 10346 AN: 1460980 Hom.: 63 Cov.: 33 AF XY: 0.00695 AC XY: 5052 AN XY: 726870

African (AFR) AF: 0.000896 AC: 30 AN: 33464

American (AMR) AF: 0.00264 AC: 118 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00244 AC: 210 AN: 86226

European-Finnish (FIN) AF: 0.00990 AC: 529 AN: 53414

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00811 AC: 9008 AN: 1111220

Other (OTH) AF: 0.00578 AC: 349 AN: 60362

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00573 AC XY: 427 AN XY: 74478

African (AFR) AF: 0.000938 AC: 39 AN: 41558

American (AMR) AF: 0.00464 AC: 71 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00929 AC: 632 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00750 Hom.: 15

Bravo AF: 0.00546

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00632 AC: 767

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00694

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	1	3	not specified (4)
-	1	1	Gaucher disease (2)
-	1	1	Gaucher disease perinatal lethal (2)
-	1	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.73
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.28	B
Vest4		0.18
MVP		0.89
MPC		0.90
ClinPred		0.0098	T
GERP RS		3.6
Varity_R		0.13
gMVP		0.84
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0078
dbscSNV1_RF	Benign	0.094
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: rs75548401; hg19: chr1-155206037; COSMIC: COSV100516534; COSMIC: COSV100516534;