rs28935197

Variant names:

• chrX-101398942-T-C
• rs28935197
• NM_000169.3:c.644A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 19P and 4B. PS3 PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong BS2

The NM_000169.3(GLA):​c.644A>G​(p.Asn215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,089,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000543776: Experimental studies have shown that this missense change affects GLA function (PMID:16773563, 17555407, 21598360)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N215H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000035 (0 hom. 11 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 8.02
• Publications: 219 publications found

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000543776: Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 21598360).; SCV001422796: "In vitro functional studies provide evidence of decreased enzymatic activity and protein stability, and therefore the p.Asn215Ser variant may impact protein function." PMID: 23935525, 23568732, 21972175, 21598360, 17555407,15702404, 16773563; SCV004357520: Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells. PMID: 16773563, 17555407, 21598360; SCV004821932: Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360).; SCV000207827: Published functional studies demonstrate a damaging effect as this variant is associated with reduced alpha-galactosidase A enzyme activity compared to wild-type (Spada et al. 2006; Wu et al. 2011); SCV000925088: Given the strong case data and functional studies demonstrating impaired alpha-galactosidase enzyme activity we consider this variant to be disease-causing and we do feel it is suitable for establishing a diagnosis/carrier status of Fabry disease and assessing risk in healthy relatives ("predictive genetic testing").; SCV004563354: Functional analyses demonstrate that enzyme with this variant has reduced stability/activity (Ishii 2007, Spada 2006).; SCV000739938: In several functional in vitro analyses, this alteration has demonstrated a reduction in alpha-galactosidase A enzyme activity, suggesting variable expressivity among clinical phenotypes depending on residual enzyme activity (Spada, 2006; Wu, 2011; Ishii, 2007; Ebrahim, 2012).; SCV000198194: Multiple functional studies have shown that the p.Asn215Ser variant protein has reduced enzymatic activity (Mills 2005, Ishii 2007, Wu 2011, Ebrahim 2012, Tian 2013).
• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398941-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3910027.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant X-101398942-T-C is Pathogenic according to our data. Variant chrX-101398942-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. 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
	GLA	NM_000169.3	MANE Select	c.644A>G	p.Asn215Ser	missense	Exon 5 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.767A>G	p.Asn256Ser	missense	Exon 6 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.644A>G	p.Asn215Ser	missense	Exon 5 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.644A>G	p.Asn215Ser	missense	Exon 5 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3485T>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.767A>G	p.Asn256Ser	missense	Exon 6 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183422 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 38 AN: 1089867 Hom.: 0 Cov.: 29 AF XY: 0.0000309 AC XY: 11 AN XY: 355965

African (AFR) AF: 0.00 AC: 0 AN: 26246

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19318

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.00 AC: 0 AN: 53877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3373

European-Non Finnish (NFE) AF: 0.0000443 AC: 37 AN: 835372

Other (OTH) AF: 0.0000218 AC: 1 AN: 45783

GnomAD4 genome Cov.: 23

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Fabry disease (14)
9	-	-	not provided (9)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Fabry disease;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
CardioboostCm	Uncertain	0.59
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.048	B
Vest4		0.90
MutPred		0.80		Loss of catalytic residue at N215 (P = 0.0951)
MVP		0.99
MPC		0.73
ClinPred		0.73	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.95
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs28935197; hg19: chrX-100653930;