1-155235057-C-T

Position:

• chr1-155235057-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000157.4(GBA1):​c.1549G>A​(p.Gly517Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 15)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.49

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 Uncertain_significance. Variant got 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 1-155235057-C-T is Pathogenic according to our data. Variant chr1-155235057-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4310.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1549G>A	p.Gly517Ser	missense_variant	11/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1549G>A	p.Gly517Ser	missense_variant	11/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Cov.: 13

GnomAD4 genome Cov.: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gaucher disease type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1993

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2020

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 29, 2024

Variant summary: GBA1 c.1549G>A (p.Gly517Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 231018 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1549G>A has been reported in the literature in an individual affected with Gaucher Disease (Beutler_1993). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 8432537). ClinVar contains an entry for this variant (Variation ID: 4310). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.84
Sift	Benign	0.079	T;T;T;T
Sift4G	Benign	0.088	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.84
MutPred		0.57		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;.;
MVP		0.93
MPC		1.6
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.72
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908301; hg19: chr1-155204848;