rs150547672

chrX-101407896-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000169.3(GLA):c.8T>C(p.Leu3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,208,132 control chromosomes in the GnomAD database, including 2 homozygotes. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (1 hom. 16 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10 O:1
• Conservation: PhyloP100: 0.323

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:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a signal_peptide (size 30) in uniprot entity AGAL_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_000169.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.024546802).
• BP6: Variant X-101407896-A-G is Benign according to our data. Variant chrX-101407896-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=1}. Variant chrX-101407896-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000864 (97/112310) while in subpopulation AFR AF= 0.00301 (93/30907). AF 95% confidence interval is 0.00251. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.8T>C	p.Leu3Pro	missense_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4040A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.8T>C	p.Leu3Pro	missense_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 96 AN: 112254 Hom.: 1 Cov.: 23 AF XY: 0.000727 AC XY: 25 AN XY: 34410

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

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: 0.00

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000235 AC: 43 AN: 183334 Hom.: 0 AF XY: 0.0000885 AC XY: 6 AN XY: 67798

Gnomad AFR exome AF: 0.00319

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000867 AC: 95 AN: 1095822 Hom.: 1 Cov.: 31 AF XY: 0.0000443 AC XY: 16 AN XY: 361252

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000864 AC: 97 AN: 112310 Hom.: 1 Cov.: 23 AF XY: 0.000754 AC XY: 26 AN XY: 34476

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.000281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.0000993 Hom.: 5

Bravo AF: 0.00115

ESP6500AA AF: 0.00417 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Leu3Pro variant in GLA has not been previously reported in individuals with Fabry disease, and has been identified in 0.32% (61/19010) of African chromosomes, including 11 hemizygotes, and 0.0036% (1/28047) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150547672). This variant has been reported in ClinVar as benign by the Laboratory for Molecular Medicine (Partners Healthcare) and GeneDx, as likely benign by Invitae and Ambry Genetics, and as a VUS by Albrecht-Kossel-Institute (Medical University Rostock) and the Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) (ID:42464). 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, BP4 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2018	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2018	Variant summary: GLA c.8T>C (p.Leu3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 200269 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.0029 in the gnomAD database, including 11 hemizygotes. This frequency is not higher than expected for a pathogenic variant in GLA causing Cardiomyopathy (0.0029 vs 0.0071). c.8T>C has been reported in the literature in individuals affected with Fabry disease (Lukas 2016), however in this study, authors found normal biomarker levels in these individuals. Experimental evidence evaluating an impact on protein function also showed normal (or somewhat elevated) activity for the variant protein (Lukas 2016). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with two laboratories classifying as "benign", two classifying as "likely benign", and one classifying as "VUS". Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 29, 2015	p.Leu3Pro in exon 1 of GLA: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (26/8444) of African chromosomes i ncluding 4 hemizygous males by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org/; dbSNP rs150547672). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 28, 2020

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2018

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. -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: yes

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
CardioboostCm	Benign	0.051
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Pathogenic	2.0	D
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.64	N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.0030	B;.
Vest4		0.76
MVP		0.82
MPC		2.2
ClinPred		0.12	T
GERP RS		1.3
Varity_R		0.25
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs150547672; hg19: chrX-100662884;