chr1-155235252-A-G

Variant names:

• chr1-155235252-A-G
• rs421016
• NM_000157.4:c.1448T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM5 PP2 PP3 PP5_Very_Strong BP4

The NM_000157.4(GBA1):​c.1448T>C​(p.Leu483Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L483R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:43 O:5
• Conservation: PhyloP100: 7.95
• Publications: 1134 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: Pathogenic. The variant received 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 93449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-155235252-A-G is Pathogenic according to our data. Variant chr1-155235252-A-G is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 4288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19879305). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.1448T>C	p.Leu483Pro	missense	Exon 10 of 11	NP_000148.2
	GBA1	NM_001005741.3		c.1448T>C	p.Leu483Pro	missense	Exon 11 of 12	NP_001005741.1
	GBA1	NM_001005742.3		c.1448T>C	p.Leu483Pro	missense	Exon 11 of 12	NP_001005742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1448T>C	p.Leu483Pro	missense	Exon 10 of 11	ENSP00000357357.3
	GBA1	ENST00000327247.9	TSL:1	c.1448T>C	p.Leu483Pro	missense	Exon 11 of 12	ENSP00000314508.5
	GBA1	ENST00000948997.1		c.1514T>C	p.Leu505Pro	missense	Exon 12 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151964 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00130 AC: 324 AN: 250058 AF XY: 0.00124

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000842 AC: 123 AN: 1460902 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726764

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26118

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39658

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86214

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111332

Other (OTH) AF: 0.000149 AC: 9 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000237 AC: 36 AN: 152080 Hom.: 0 Cov.: 25 AF XY: 0.000256 AC XY: 19 AN XY: 74322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000434 AC: 18 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00253 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00315 AC: 383

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Gaucher disease type I (10)
9	-	-	not provided (9)
7	-	-	Gaucher disease (8)
5	-	-	Gaucher disease type II (5)
3	-	-	Gaucher disease type III (3)
2	-	-	Gaucher disease perinatal lethal (3)
2	-	-	Parkinson disease, late-onset (3)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset (1)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	GBA1-related disorder (1)
1	-	-	Lewy body dementia (1)
1	-	-	not specified (1)
-	-	-	Dementia, Lewy body, susceptibility to (1)
-	-	-	Movement disorder;C0234379:Resting tremor;C0242422:Parkinsonian disorder;C0749379:Thoracolumbar scoliosis;C0813217:Hypomimic face (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.035	D
Polyphen		0.94	P
Vest4		0.96
MVP		0.94
MPC		2.3
ClinPred		0.10	T
GERP RS		3.2
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs421016; hg19: chr1-155205043;