NM_000169.3:c.643_645delAATinsTCG

Variant names:

• chrX-101398941-ATT-CGA
• NM_000169.3:c.643_645delAATinsTCG
• GLA p.Asn215Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_000169.3(GLA):c.643_645delAATinsTCG (p.Asn215Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 40 pathogenic, 0 benign rare missense variants (OR vs. background: 405.0).; ±8 AA neighbourhood: 22 pathogenic, 0 benign (OR vs. background: 225.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.N215K: Likely_pathogenic (ClinVar VariationId 3910027, 1 star); Other variants at the same amino acid residue (not pathogenic): p.N215D: Uncertain_significance (ClinVar VariationId 4087448, 1 star); p.N215H: Uncertain_significance (ClinVar VariationId 179331, 2 stars)

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.643_645delAATinsTCG p.Asn215Ser	missense	N/A	Prot: NP_000160.1 UniProt:
	GLA NM_001406747.1		c.766_768delAATinsTCG p.Asn256Ser	missense	N/A	Prot: NP_001393676.1 UniProt:
	GLA NM_001406748.1		c.643_645delAATinsTCG p.Asn215Ser	missense	N/A	Prot: NP_001393677.1 UniProt:

GLA NM_000169.3

MANE Select

HGVSc / HGVSpc.643_645delAATinsTCGp.Asn215Ser

Exon rankN/A

missense

Prot: NP_000160.1UniProt: P06280Q53Y83

GLA NM_001406747.1

HGVSc / HGVSpc.766_768delAATinsTCGp.Asn256Ser

Exon rankN/A

missense

Prot: NP_001393676.1UniProt: A0A3B3IUC4

GLA NM_001406748.1

HGVSc / HGVSpc.643_645delAATinsTCGp.Asn215Ser

Exon rankN/A

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.643_645delAATinsTCG p.Asn215Ser	missense	N/A	Prot: ENSP00000218516.4 UniProt:
	RPL36A-HNRNPH2 ENST00000409170.3	TSL:4	c.300+3484_300+3486delATTinsCGA	intron	Intron 4 of 4	Prot: ENSP00000386655.4 UniProt:
	GLA ENST00000649178.1		c.766_768delAATinsTCG p.Asn256Ser	missense	N/A	Prot: ENSP00000498186.1 UniProt:

GLA ENST00000218516.4

TSL:1MANE Select

HGVSc / HGVSpc.643_645delAATinsTCGp.Asn215Ser

Exon rankN/A

missense

Prot: ENSP00000218516.4UniProt: P06280

RPL36A-HNRNPH2 ENST00000409170.3

TSL:4

HGVSc / HGVSpc.300+3484_300+3486delATTinsCGA

Exon rankIntron 4 of 4

intron

Prot: ENSP00000386655.4UniProt: H7BZ11

GLA ENST00000649178.1

HGVSc / HGVSpc.766_768delAATinsTCGp.Asn256Ser

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chrX-100653929;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar