rs1064651

Variant names:

• chr1-155235727-C-G
• rs1064651
• NM_000157.4:c.1342G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-155235727-C-G
• chr1-155235727-C-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP2 PP5_Very_Strong

The NM_000157.4(GBA1):​c.1342G>C​(p.Asp448His) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003922073: experimental studies have shown that this missense change affects GBA function (Xu, Y H et al., 2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D448V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 5.37
• Publications: 310 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003922073: experimental studies have shown that this missense change affects GBA function (Xu, Y H et al., 2011).; SCV001423055: Animal models in mice have shown that this variant causes Gaucher disease based on visceral disease and decreased beta-glucosidase levels (PMID: 16061944).; SCV000329943: Functional analysis of D448H found that it is associated with significantly reduced beta-glucocerebrosidase enzyme activity (Grace et al., 1994); PMID: 19816973, 9040001, 19286695, 9061570, 10447266, 10796875, 11992489, 23588557, 16293621, 21742527, 2269438, 21700325, 15146461, 29934114, 30637984, 31709146, 31996268, 8294487, 22975760, 21745757, 24126159, 20816920, 7627184, 10360404, 21472771, 21257328, 8544197, 27312774, 26096741, 27717005, 25946768, 26887759, 29656334, 28894968, 10714667, 14578207, 8160756, 30528841, 31026225, 28393750, 31130326, 30410382, 28040394, 31216804, 31589614, 32677286, 9556036, 32618053, 33763395, 33176831, 32658388, 32714263; SCV000964937: Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 16293621, 21257328).; SCV002755388: Both in vivo and in vitro studies have shown that this mutation demonstrates reduced enzyme activity (4- 9% of wild type) (Montfort et al. Hum. Mutat. 2004;23(6):567-75).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235726-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4294.Status of the report is no_assertion_criteria_provided, 0 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 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 1-155235727-C-G is Pathogenic according to our data. Variant chr1-155235727-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1342G>C	p.Asp448His	missense	Exon 9 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1342G>C	p.Asp448His	missense	Exon 10 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1342G>C	p.Asp448His	missense	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.1342G>C	p.Asp448His	missense	Exon 9 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1342G>C	p.Asp448His	missense	Exon 10 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1408G>C	p.Asp470His	missense	Exon 11 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152014 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250360 AF XY: 0.000126

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461294 Hom.: 0 Cov.: 32 AF XY: 0.0000922 AC XY: 67 AN XY: 726862

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

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.000247 AC: 11 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39692

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86138

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111738

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

⚠️ 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 AF: 0.000197 AC: 30 AN: 152130 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74370

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

African (AFR) AF: 0.000217 AC: 9 AN: 41390

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000840617), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000321 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Gaucher disease type I (7)
3	-	-	Gaucher disease (4)
3	-	-	Gaucher disease perinatal lethal (3)
2	-	-	Gaucher disease type II (2)
2	-	-	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (2)
2	-	-	Parkinson disease, late-onset (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 (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	-	-	Gaucher disease type III (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.048
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.74
Sift	Benign	0.069	T
Sift4G	Benign	0.091	T
Polyphen		0.20	B
Vest4		0.65
MVP		0.97
MPC		0.93
ClinPred		0.16	T
GERP RS		3.5
Varity_R		0.76
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 46

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

Other links and lift over

dbSNP: rs1064651; hg19: chr1-155205518; COSMIC: COSV59168989; COSMIC: COSV59168989;