rs76763715

Variant names:

• chr1-155235843-T-C
• rs76763715
• NM_000157.4:c.1226A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-155235843-T-C
• chr1-155235843-T-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 17P and 5B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4 BS2

The ENST00000368373.8(GBA1):​c.1226A>G​(p.Asn409Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.002 in 1,613,914 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic,risk factor (★★). ClinVar reports functional evidence for this variant: "SCV000238464: Alleles with this mutation have been shown to have lower activity compared to the wildtype (Grace et al. 1994, PMID:23510062" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N409K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: GBA1 ENST00000368373.8 missense, splice_region
• Scores: Splicing: ADA: 0.5713
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:50 U:1 O:6
• Conservation: PhyloP100: 4.36
• Publications: 1161 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: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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: Genomics England PanelApp, Orphanet
• 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238464: Alleles with this mutation have been shown to have lower activity compared to the wildtype (Grace et al. 1994, PMID: 23510062; Montfort et al. 2004, PMID: 15146461).; SCV000538031: Several functional studies have shown this variant to have reduced catalytic activity (by 81-95%) (Babajani et al. 2012).; SCV001441565: Numerous functional studies have demonstrated that this variant causes reduced enzyme activity compared to wild-type protein.; SCV002034836: In vitro functional studies have demonstrated reduced enzymatic activity for p.Asn409Ser compared to wild-type protein (Montfort et al. 2004; Malini et al. 2014).; SCV002318968: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15826241; 16293621; 15605411)"; SCV000321702: Published functional studies demonstrate that the defective protein shows reduced activity compared to wildtype (Grace et al., 1994; Malini et al., 2014); SCV000936391: Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 22160715, 22592100).; SCV001471102: Functional studies demonstrate this variant has reduced enzymatic activity (Grace 1994, Tsuji 1988).; SCV000697577: Functional study showed variant with 13.3% of WT activity (Grace_1994).; SCV001423049: "In vitro functional studies showing reduced enzymatic activity, increased a-synuclein concentration, restoration of enzymatic activity through molecular chaperones, and a shifted optimal pH for enzymatic activity provide some evidence that the p.Asn409Ser variant may impact protein function (PMID: 14757438, 21472771, 28923368, 20980259)."; SCV004046061: Functional studies indicate that this variant reduces enzyme activity of the GBA protein (PMID: 22592100, 8294487, 22160715).; SCV005900331: At least one patient with this variant displayed deficient glucocerebrosidase (glucosylceramidase) enzyme activity in fibroblasts, which is highly specific for Gaucher disease (PMID: 8294487, 15826241). Reduced enzyme activity and abnormal protein function has also been demonstrated in heterologous expression systems indicating that this variant impacts protein function (PMID: 8294487, 22160715).; SCV004796704: "In vitro functional studies indicated that this variant results in loss of enzyme activity (see for example, Tsuji et al. 1988. PubMed ID: 3353383; Sidransky et al. 2009. PubMed ID: 19846850)."; SCV002755618: A functional study found that Sf9 cells containing this mutation expressed significantly less protein when compared to wild-type (Montfort, 2004).; SCV005045123: Functional studies show reduced enzyme activity and increased levels of alpha-synuclein protein, indicating that this variant impacts protein function (Fernandes HJR et al., PMID: 26905200; Woodard CM et al., PMID: 25456120).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000368373.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235842-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 594893.
• 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 type I, Gaucher disease type III, Gaucher disease type II, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease perinatal lethal, Gaucher disease, Parkinson disease.
• PP5: Variant 1-155235843-T-C is Pathogenic according to our data. Variant chr1-155235843-T-C is described in ClinVar as Pathogenic/Likely_pathogenic|risk_factor. ClinVar VariationId is 4290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01917398). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000368373.8. 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.1226A>G	p.Asn409Ser	missense splice_region	Exon 9 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1226A>G	p.Asn409Ser	missense splice_region	Exon 10 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1226A>G	p.Asn409Ser	missense splice_region	Exon 10 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1226A>G	p.Asn409Ser	missense splice_region	Exon 9 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1226A>G	p.Asn409Ser	missense splice_region	Exon 10 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1292A>G	p.Asn431Ser	missense splice_region	Exon 11 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 151930 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00231 AC: 581 AN: 251444 AF XY: 0.00230

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00201 AC: 2941 AN: 1461866 Hom.: 5 Cov.: 32 AF XY: 0.00199 AC XY: 1445 AN XY: 727230

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 738 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00172 AC: 1915 AN: 1111986

Other (OTH) AF: 0.00306 AC: 185 AN: 60396

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152048 Hom.: 3 Cov.: 30 AF XY: 0.00165 AC XY: 123 AN XY: 74322

African (AFR) AF: 0.000193 AC: 8 AN: 41452

American (AMR) AF: 0.00118 AC: 18 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 67974

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00244 Hom.: 1

Bravo AF: 0.00195

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00221 AC: 268

EpiCase AF: 0.00267

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	Gaucher disease type I (17)
13	-	-	not provided (13)
6	-	-	Gaucher disease (8)
4	-	-	Parkinson disease, late-onset (5)
2	-	-	Gaucher disease perinatal lethal (2)
2	-	-	GBA1-related disorder (2)
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 (2)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	Lewy body dementia (1)
1	-	-	Lewy body dementia;C3160718:Parkinson disease, late-onset (1)
1	-	-	not specified (1)
1	-	-	Rigidity;C0085623:Akinesia (1)
-	1	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)
-	-	-	Dementia, Lewy body, susceptibility to (1)
-	-	-	Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.086
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.033	D
Polyphen		0.61	P
Vest4		0.64
MVP		0.93
MPC		1.0
ClinPred		0.031	T
GERP RS		3.5
Varity_R		0.59
gMVP		0.85
Mutation Taster		=44/56	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76763715; hg19: chr1-155205634;