rs77369218

Positions:

• chr1-155235726-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000157.4(GBA1):​c.1343A>T​(p.Asp448Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D448H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.39

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235727-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 1-155235726-T-A is Pathogenic according to our data. Variant chr1-155235726-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4294.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1343A>T	p.Asp448Val	missense_variant	9/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1343A>T	p.Asp448Val	missense_variant	9/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gaucher disease type I Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 21, 2015

- -

Gaucher disease type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 18, 2022

- -

Gaucher disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.95	P;P;.;.
Vest4		0.92
MutPred		0.60		Gain of methylation at K447 (P = 0.0363);Gain of methylation at K447 (P = 0.0363);.;.;
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs77369218; hg19: chr1-155205517;