rs75548401

chr1-155236246-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 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. 13/22 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
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4
• 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 id is 93447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=2}. Variant chr1-155236246-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1223C>T	p.Thr408Met	missense_variant, splice_region_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1223C>T	p.Thr408Met	missense_variant, splice_region_variant	8/11	1	NM_000157.4	P1

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

GnomAD3 exomes AF: 0.00594 AC: 1491 AN: 251106 Hom.: 7 AF XY: 0.00583 AC XY: 792 AN XY: 135750

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 SAS exome AF: 0.00245

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

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00244

Gnomad4 FIN exome AF: 0.00990

Gnomad4 NFE exome AF: 0.00811

Gnomad4 OTH exome AF: 0.00578

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

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00929

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00820 Hom.: 11

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 32658388, 33281709, 32618053, 29487000, 28966932, 29842932, 30548430, 30146349, 30302829, 29396846, 28834018, 29140481, 27153395, 27648471, 28030538, 26000814, 27094865, 8774051, 22001711, 18987351, 22173904, 12694238) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GBA1: BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 02, 2018	Variant summary: The GBA c.1223C>T (p.Thr408Met, also known as Thr369Met) variant located in the glycosyl hydrolase family 30, TIM-barrel domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value). This variant was found in 1708/277314 (7 homozygotes) control chromosomes (gnomAD and publication controls) at a frequency of 0.0061591, which is approximately 1 times the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals including a co-occurrence with another pathogenic GBA variant, D409H (also known as D448H - scored DV)(Hodanova_1999). Another publication, Walker_2003, cites the variant, T369M, as a polymorphism. A publication, Hodanova_2003, does indicate the variant could cause a functional impact but the authors state that at most would be a mild mutation even on the verge of a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 05, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Gaucher disease Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Thr408Met variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 12734541, 12694238, 10796875) and has been identified in 0.992% (249/25102) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75548401). This variant has also been reported in ClinVar (VariationID: 93447) as a VUS by DST/NWU Preclinical Drug Development Platform, as likely benign by CeGaT Praxis fuer Humangnetik Tuebingen and Children's Mercy Hospital and Clinics, and as benign by PreventionGenetics, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Thr408Met variant may not impact protein function (PMID: 12734541). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was reported with a reported pathogenic variant in an unknown phase in 2 individuals with Gaucher disease (VariationID: 4290; PMID: 12734541, 10796875). However, this variant was also found in cis with other pathogenic variants, suggesting that it may not cause disease (VariationID: 65570, 4293; PMID: 12734541, 12694238). In summary, the clinical significance of the p.Thr408Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, BP2, BS3_supporting (Richards 2015). -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 14, 2017	- -

Gaucher disease perinatal lethal Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 28, 2018	This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Parkinson disease, late-onset Uncertain:1

Uncertain significance, no assertion criteria provided

research

DST/NWU Preclinical Drug Development Platform, North-West University

Sep 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;D;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.0	M;M;.;.
MutationTaster	Benign	0.60	N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.28	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs75548401; hg19: chr1-155206037; COSMIC: COSV100516534; COSMIC: COSV100516534;