X-101398942-T-C

Variant names:

• chrX-101398942-T-C
• rs28935197
• NM_000169.3:c.644A>G
• GLA p.Asn215Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO6_SupportingO7_ModerateO8_Supporting

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 cumulative frequency of 0.0000349 (AC=38) in the gnomAD database across 1,089,867 control chromosomes, including 11 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.0000327. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). Variant has been reported in ClinVar as Pathogenic/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. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.N215K: Likely_pathogenic (ClinVar VariationId 3910027, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N215D: Uncertain_significance (ClinVar VariationId 4087448, 1 star); p.N215H: Uncertain_significance (ClinVar VariationId 179331, 2 stars) This exact variant is curated in the UniProt human variants database 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:27
• Conservation: PhyloP100: 8.02
• Publications: 235 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]

GLA Gene-Disease associations (from GenCC):

• Fabry disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen

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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000033 — very rare (O3 supporting [+1])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 40 pathogenic, 0 benign (OR vs. background: 405.0).; ±8 AA neighbourhood: 22 pathogenic, 0 benign (OR vs. background: 225.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: not available (stub — GNOMAD_MISSENSE_Z_SCORE not provided); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated classification 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	Prot: NP_000160.1 UniProt:
	GLA NM_001406747.1		c.767A>G p.Asn256Ser	missense	Exon 6 of 8	Prot: NP_001393676.1 UniProt:
	GLA NM_001406748.1		c.644A>G p.Asn215Ser	missense	Exon 5 of 6	Prot: NP_001393677.1 UniProt:

GLA NM_000169.3

MANE Select

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 7

missense

Prot: NP_000160.1UniProt: P06280Q53Y83

GLA NM_001406747.1

HGVSc / HGVSpc.767A>Gp.Asn256Ser

Exon rankExon 6 of 8

missense

Prot: NP_001393676.1UniProt: A0A3B3IUC4

GLA NM_001406748.1

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 6

missense

Prot: NP_001393677.1UniProt: A0A6Q8PHD1

Ensembl Transcripts

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

GLA ENST00000218516.4

TSL:1MANE Select

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 7

missense

Prot: ENSP00000218516.4UniProt: P06280

RPL36A-HNRNPH2 ENST00000409170.3

TSL:4

HGVSc / HGVSpc.300+3485T>C

Exon rankIntron 4 of 4

intron

Prot: ENSP00000386655.4UniProt: H7BZ11

GLA ENST00000649178.1

HGVSc / HGVSpc.767A>Gp.Asn256Ser

Exon rankExon 6 of 8

missense

Prot: ENSP00000498186.1UniProt: A0A3B3IUC4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD2 exomes	AF: 0.00000545	AC:1	Hom:	AN:183422	Cov:
GnomAD4 exome	AF: 0.0000349	AC:38	Hom:0	AN:1089867	Cov:29
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00215	AC:104	Hom:0	AN:48418	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41944	0.0000299	2	66798
SCHEMA(Schizophrenia)	0.0000295	2	67786	0.00	0	133138

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Fabry disease (15)
9	-	-	not provided (9)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Fabry disease;C0007194:Hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
CardioboostCm	Uncertain	0.59
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.47
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	29/71	disease causing (ClinVar)
MutationAssessor	Uncertain	2.8	M
PhyloP100	Pathogenic	8.0
popEVE	Benign	-4.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.87
VESM-3B	Benign	-8.0

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28935197;

hg19: chrX-100653930;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar