rs201449986

Variant names:

• chrX-101407856-A-C
• rs201449986
• NM_000169.3:c.48T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-101407856-A-C
• chrX-101407856-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000169.3(GLA):​c.48T>G​(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,210,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 89 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L16L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00031 (0 hom. 85 hem.)
• Consequence: GLA NM_000169.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.0120
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-101407856-A-C is Benign according to our data. Variant chrX-101407856-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42455.
• BP7: Synonymous conserved (PhyloP=-0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000116 (13/112283) while in subpopulation NFE AF = 0.000207 (11/53187). AF 95% confidence interval is 0.000116. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.48T>G	p.Leu16Leu	synonymous	Exon 1 of 7	NP_000160.1
	GLA	NM_001406747.1		c.48T>G	p.Leu16Leu	synonymous	Exon 1 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.48T>G	p.Leu16Leu	synonymous	Exon 1 of 6	NP_001393677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.48T>G	p.Leu16Leu	synonymous	Exon 1 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4080A>C		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.48T>G	p.Leu16Leu	synonymous	Exon 1 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 112226 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000938

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.000660

GnomAD2 exomes AF: 0.000196 AC: 36 AN: 183415 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000307 AC: 337 AN: 1097748 Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 85 AN XY: 363104

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.000199 AC: 7 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.000385 AC: 324 AN: 841701

Other (OTH) AF: 0.000130 AC: 6 AN: 46073

GnomAD4 genome AF: 0.000116 AC: 13 AN: 112283 Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4 AN XY: 34425

African (AFR) AF: 0.00 AC: 0 AN: 30939

American (AMR) AF: 0.0000937 AC: 1 AN: 10674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53187

Other (OTH) AF: 0.000651 AC: 1 AN: 1535

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.000128

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Benign:7

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

GLA c.48T>G is a synonymous (silent) variant that retains Leucine at residue 16. This variant has been observed in at least one proband affected with Fabry disease (PMID: 27585509; 34118938). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID: 26866599; 27585509). This synonymous variant is not predicted to impact splicing and does not affect a conserved nucleotide. It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify GLA c.48T>G as a likely benign variant.

May 29, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

The c.48T>G variant in GLA has not been previously reported in individuals with Fabry disease, and has been identified in 0.039% (36/92630) of European (non-Finnish) chromosomes, including 5 hemizygotes, 0.019% (1/5335) of other chromosomes, and 0.011% (3/28053) of Latino chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201449986). This variant has also been reported in ClinVar as likely bengin by the Laboratory for Molecular Medicine (Partners Healthcare), GeneDx, and Invitae and a VUS by Illumina Clinical Services Laboratory (ID:42455). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP7 (Richards 2015).

not provided Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26866599)

Jul 29, 2025

Revvity Omics, Revvity

Significance: Likely benign

Review Status: flagged submission

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLA: BP4, BP7, BS2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Jan 21, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu16Leu in exon 1 of GLA: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1/6728 European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.ed/EVS/;). Leu16Leu in exon 1 of GLA (allele frequency = 1/6728) **

GLA-related disorder Benign:1

Jun 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hypertrophic cardiomyopathy Benign:1

Sep 29, 2022

Cohesion Phenomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Nov 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.6
DANN	Benign	0.61
PhyloP100		-0.012
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201449986; hg19: chrX-100662844;