X-101407856-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000169.3(GLA):​c.48T>C​(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L16L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120
• 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]

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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-101407856-A-G is Benign according to our data. Variant chrX-101407856-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2772252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.012 with no splicing effect.

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>C	p.Leu16Leu	synonymous	Exon 1 of 7	NP_000160.1
	GLA	NM_001406747.1		c.48T>C	p.Leu16Leu	synonymous	Exon 1 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.48T>C	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>C	p.Leu16Leu	synonymous	Exon 1 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4080A>G		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.48T>C	p.Leu16Leu	synonymous	Exon 1 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Benign:1

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.8
DANN	Benign	0.62
PhyloP100		-0.012
PromoterAI		-0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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;